PubMed：

(tuberculosis[Title/Abstract]) OR (lung cancer [Title/ Abstract])

Filters applied: from 2025/11/1 - 2025/11/30.

1. J Control Release. 2025 Nov 10;387:114199. doi: 10.1016/j.jconrel.2025.114199. Epub 2025 Sep 4.

Targeting HMGB1 modulates cancer-associated fibroblasts and enhances radiotherapy in lung adenocarcinoma.

Radio-resistance remains a major challenge in the effective treatment of lung cancer. Cancer-associated fibroblasts (CAFs), the predominant cellular components in solid tumors, play a crucial role in tumor treatment and resistance. Thus, understanding the interactions between CAFs and tumor cells is key to overcoming radio-resistance in lung cancer. Herein, we demonstrated that radiation exacerbates fibrosis and acted as a critical driver for fibroblast proliferation and migration by promoting tumor cell secretion of high mobility group box 1(HMGB1), a key regulator of tumor progression and metastasis. Mechanistic analysis revealed that HMGB1 activated the PI3K-AKT pathway via TLR4, driving the transformation of CAFs into myCAFs subtypes. To block HMGB1 and enhance radiotherapy, we encapsulated the HMGB1 inhibitor DPG into tumor-targeted liposomes (DPG-RGDLipo) for combined tumor radiotherapy. The results showed that HMGB1 inhibition not only prevented CAFs activation and boosted radiotherapy effectiveness but also promoted immune infiltration, including CD8+ T cells and DCs. Additionally, the reduction of MMP2 and VEGF in tumor tissues further suggested that combined targeted therapy could also inhibit tumor metastasis and invasion. Our findings reveal the relationship between lung cancer radio-resistance and CAFs, highlighting the significance of targeting HMGB1 to inhibit CAFs in enhancing radiotherapy sensitivity.

PMID: 40914483 [Indexed for MEDLINE]

2. J Thorac Oncol. 2025 Nov;20(11):1582-1593. doi: 10.1016/j.jtho.2025.06.012. Epub 2025 Aug 5.

Molecular Landscape and Therapeutic Strategies of Lung Cancer Lineage Plasticity.

Histologic transformation from lung adenocarcinoma (LUAD) to SCLC or lung squamous cell carcinoma (LUSC) represents distinct but converging processes of cellular plasticity. Cellular plasticity, the ability to switch phenotypes between distinct developmental lineages, is critical in embryogenesis, tissue repair, and homeostasis. Tumor cells exploit these mechanisms to adapt to external pressures, such as therapeutic interventions, resulting in phenotypic transitions that drive therapeutic resistance and poor prognosis. LUAD cells that undergo transformation to SCLC or LUSC demonstrate unique and overlapping genetic, transcriptomic, epigenetic, and immune microenvironment changes that underscore the convergence and divergence of these processes. Although the histologic transition of LUAD to SCLC and LUSC is increasingly recognized as a mechanism of resistance to targeted therapies in lung cancer, the molecular drivers of the transformation process remain poorly understood. This review highlights the current knowledge of the molecular drivers, transcriptional and epigenetic programs, and immune interactions underlying these transformations, offering insights into potential therapeutic targets to mitigate resistance mechanisms.

PMID: 40751717 [Indexed for MEDLINE]

3. Cell. 2025 Dec 11;188(25):7083-7098.e18. doi: 10.1016/j.cell.2025.10.020. Epub 2025 Nov 7.

Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction.

Biomarkers accurately informing prognostic assessment and therapeutic strategy are critical for improving patient outcome in oncology. Here, we apply a whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection approach to address this challenge, leveraging 1,800 variants across 2,994 plasma samples from 431 patients with non-small cell lung cancer (NSCLC) from the TRACERx study. We show that ultrasensitive ctDNA detection below 80 parts per million both pre- and postoperatively is highly prognostic, and combinatorial analysis of the pre- and postoperative ctDNA status identifies an intermediate risk group, improving disease stratification. ctDNA kinetics demonstrate clinical utility during adjuvant therapy, where patients that "clear" ctDNA during adjuvant therapy experience improved outcomes. Moreover, characterization of patterns in postoperative ctDNA kinetics reveals insights into the timing, risk, and anatomical pattern of relapses. By incorporating longitudinal ultrasensitive ctDNA detection, we propose a refined schema for guiding the stratification and treatment recommendations in early stage NSCLC.

PMID: 41205598 [Indexed for MEDLINE]

4. Cancer Res. 2025 Nov 14;85(22):4469-4484. doi: 10.1158/0008-5472.CAN-25-0405.

Neuropeptide Precursor VGF Promotes Neuroendocrine Differentiation and Cancer-Associated Fibroblast Activation in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Neuroendocrine differentiation is a prominent feature of SCLC. This study identified VGF, a secreted neuropeptide precursor, as a critical regulator of neuroendocrine differentiation in SCLC, particularly the achaete-scute homolog 1 (ASCL1)+ subtype. VGF orchestrated upregulation of the transcription factor ASCL1 through a cAMP-responsive element-binding protein-dependent mechanism, thereby promoting neuroendocrine differentiation. Furthermore, VGF mediated the transformation of fibroblasts into cancer-associated fibroblasts (CAF), establishing metabolic coupling between SCLC cells and CAFs via lactate exchange. A therapeutic strategy targeting VGF and monocarboxylate transporter 1 disrupted neuroendocrine differentiation and SCLC-CAF metabolic coupling, demonstrating significant efficacy in both in vitro and in vivo models. Together, this study provides insights into the mechanisms underlying SCLC neuroendocrine differentiation and reveals targets and therapeutic strategies for advanced SCLC.

SIGNIFICANCE: VGF is a therapeutic target in small cell lung cancer that promotes expression of ASCL1 to drive neuroendocrine differentiation and mediates lactate exchange between cancer cells and fibroblasts in the tumor microenvironment.

PMID: 40857617 [Indexed for MEDLINE]

5. Cell Stem Cell. 2025 Dec 4;32(12):1869-1885.e8. doi: 10.1016/j.stem.2025.10.005. Epub 2025 Nov 3.

Senolytic-sensitive p16(Ink4a)+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Update of

    bioRxiv. 2024 Jul 30:2024.07.29.605645. doi: 10.1101/2024.07.29.605645.

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

PMID: 41187746 [Indexed for MEDLINE]

6. Nat Commun. 2025 Nov 21;16(1):10244. doi: 10.1038/s41467-025-64839-4.

Cancer cell-derived IL-1β reverses chemo-immunotherapy resistance in non-small cell lung cancer.

Many non-small cell lung cancer (NSCLC) patients remain unresponsive to the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies. While interleukin (IL)-1β is known to promote lung cancer growth in humans and mice, we show here that IL-1β administration or overexpression overcomes resistance to classical chemo-immunotherapy (cisplatin/pemetrexed/anti-PD-1) in mouse lung cancer models. The antitumor effects of IL-1β rely on cancer cell-derived CXCL10 which mediates CD8 T cell recruitment at the tumor site. In lung cancer cells, Thioredoxin Interacting Protein (TXNIP) induces mitochondrial DNA (mtDNA) release in the cytosol, activating Absence in Melanoma 2 (AIM2) inflammasome, which subsequently triggers IL-1β and CXCL10 secretion, thereby reversing chemo-immunotherapy resistance. The clinical relevance of our findings is supported by the transcriptomic analysis of patient tumors, showing that high expression of IL1B, IL1R1, AIM2 and/or TXNIP is associated with better response to immunotherapy in NSCLC patients. Additionally, drug screening identifies MEK and MDM2 inhibitors as inducers of TXNIP expression capable of reversing resistance to chemo-immunotherapy. This study highlights a positive role of IL-1β in lung cancer treatment and suggests that enhancing IL-1β production at the tumor site can overcome resistance to chemo-immunotherapy.

PMID: 41271647 [Indexed for MEDLINE]

7. J Thorac Oncol. 2025 Nov;20(11):1716-1721. doi: 10.1016/j.jtho.2025.07.122. Epub 2025 Jul 26.

Comprehensive Genomic Profiling of Rare Lung Tumors: Adenosquamous Carcinoma and Pulmonary Carcinosarcoma.

In 2025, lung cancer remains the leading cause of cancer-related mortality in both men and women. Although the advent of immunotherapy and targeted therapies has revolutionized the treatment of NSCLC, treatments for rare histologic types such as adenosquamous carcinoma and pulmonary carcinosarcoma remain limited owing to insufficient data on molecular profiling. As such, knowledge of the molecular characteristics of rare tumors to inform treatment modalities for targeted approaches is desperately needed. In collaboration with Caris Life Sciences, we present new molecular profiling data including genomic, transcriptomic, and the current landscape of surrogate biomarkers to predict response to immunotherapy for ASC and PC to aid in expanding knowledge of these rare tumors and expediting novel therapies.

PMID: 40721085 [Indexed for MEDLINE]

8. JAMA Oncol. 2025 Nov 1;11(11):1385-1392. doi: 10.1001/jamaoncol.2025.2891.

Current Controversies and Challenges in Non-Oncogene-Addicted Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Review.

IMPORTANCE: It has been stated that especially with the advancements in imaging, systemic therapy, and local radical treatment (LRT) that patients with synchronous oligometastatic disease (sOMD) can potentially benefit from curative-intent treatment. This statement is challenged by the results of the NRG-LU002 randomized phase 2/3 trial, showing no significant progression-free survival and overall survival improvements with the addition of LRT to maintenance systemic therapy in patients with oligometastatic non-small cell lung cancer (NSCLC) who achieved at least stable disease after induction systemic therapy (approximately 90% received an immunotherapy-based regimen). This Review discusses the current challenges and controversies in the treatment of non-oncogene-addicted sOMD.

OBSERVATIONS: Whether LRT indeed can improve survival in a contemporary immunotherapy-based systemic treatment regimen is discussed as well as the optimal treatment sequence. Moreover, the NRG-LU002 trial also sparks debate of whether a true sOMD state exists. Genomic alterations, the tumor microenvironment of the primary tumor and metastasis, organotropism, and tumor heterogeneity can all influence metastatic potential, giving a biological explanation that there could be existence of a true sOMD state. However, as true sOMD cannot be distinguished from early-detected widespread metastatic disease with the current imaging modalities, it becomes difficult to select patients for a radical strategy and protect patients from futile treatment.

CONCLUSIONS AND RELEVANCE: It remains under debate whether synchronous oligometastatic NSCLC represents a distinct biological entity or merely a probabilistic imaging finding. Biomarkers such as circulating tumor DNA, microRNA, and radiomics may improve patient selection but require further validation. Clinical trials should prioritize translational research to address these challenges.

PMID: 40906489 [Indexed for MEDLINE]

9. Adv Mater. 2025 Nov;37(47): e02375. doi: 10.1002/adma.202502375. Epub 2025 Sep 1.

A Synergistic 3D-Printed Collar Transforms Radiofrequency Ablation Into Potent Thermal Immunotherapy for Lung Cancer.

Interventional thermal therapy, such as radiofrequency ablation (RFA), is a preferred therapy for non-small cell lung cancer (NSCLC) patients. However, part of some patients will still suffer from tumor recurrence due to incomplete ablation (e.g., restricted thermal conductivity, etc.). Notably, RFA can evoke anti-tumor immunity by releasing tumor-associated antigens (TAAs), but this effect is weak. Herein, to boost thermal and immune therapeutic efficiency for complete tumor eradication, an effective nano-adjuvant (CpG-pIL12-LDHs, LC12), layered double hydroxides (LDHs) carrying immune stimulators, CpG ODN (CpG) and IL-12 plasmid (pIL-12), is developed, which is further integrated into a 3D-printed collar for eliciting potent thermotherapy and therapeutic vaccine against lung cancer. The as-prepared 3D-printed adjuvant collar (3D-LC12) can be attached to the RFA electronic needle and respond to the radiofrequency electrical field during treatment, enhancing ablation temperature, area, and nano-adjuvant's diffusion. After release from the temperature-sensitive collar, LC12 can form an in situ therapeutic cancer vaccine, activate APCs, and remodel the tumor microenvironment (TME), triggering a robust antitumor immune response. Therefore, the current study demonstrates a multi-functional 3D-printed adjuvant collar for efficient eradication of lung cancer via one-time RFA-integrated therapy, providing a novel combined strategy for interventional thermal therapy against tumors.

PMID: 40891114 [Indexed for MEDLINE]

10. Adv Sci (Weinh). 2025 Nov;12(42): e00838. doi: 10.1002/advs.202500838. Epub 2025 Aug 19.

The GGH/HuR Complex Binds and Stabilizes mRNAs to Maintain Tumor Cell Cycle and DNA Replication.

GGH (Gamma-glutamyl hydrolase) is a folate metabolism enzyme that hydrolyzes intracellular polyglutamylated folates and is highly expressed in various cancers. It remains unclear whether GGH functions as an oncogene and its underlying mechanisms in tumor progression. Here, it is reported that GGH silencing inhibited the growth of lung cancer cells in vivo and in vitro. The oncogenic function of GGH relied on its non-canonical role as a novel RNA-binding protein, which maintained the cell cycle and DNA replication by stabilizing target mRNAs. Furthermore, GGH bound to the GC-rich motif in the 5' untranslated region of mRNAs, such as CDC6 and CCND1. Additionally, GGH directly interacts with HuR (Human Antigen R), a well-characterized RNA-binding protein critical for mRNA stability in cancer. GGH, HuR, and their mRNA targets formed a ternary complex, which may facilitate the induction of a circular mRNA conformation, potentially enhancing RNA stability. Finally, it is found that GGH is highly expressed in lung cancer tissues, and its elevated expression correlates with worse patient survival in lung cancer. This discovery offered novel insights and identified potential therapeutic targets for the prevention and treatment of lung cancer.

PMID: 40831251 [Indexed for MEDLINE]

11. Cancer Commun (Lond). 2025 Nov;45(11):1547-1578. doi: 10.1002/cac2.70068. Epub 2025 Oct 13.

CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer.

BACKGROUND: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy.

METHODS: We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24.

RESULTS: CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression.

CONCLUSIONS: CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.

PMID: 41084191 [Indexed for MEDLINE]

12. Cell Metab. 2025 Nov 4;37(11):2233-2249.e9. doi: 10.1016/j.cmet.2025.10.001. Epub 2025 Oct 24.

Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.

Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.

PMID: 41138721 [Indexed for MEDLINE]

13. Lancet Oncol. 2025 Dec;26(12):1541-1551. doi: 10.1016/S1470-2045(25)00490-5. Epub 2025 Nov 10.

Effectiveness of NELSON versus PLCOm2012 lung cancer screening eligibility criteria in Germany (HANSE): a prospective cohort study.

BACKGROUND: Low-dose chest CT screening can reduce lung cancer mortality through early diagnosis. Several studies suggest that risk prediction models are more efficient than categorical age and smoking criteria for participant selection, but there are still reservations from policy makers about their implementation. We aimed to compare the effectiveness of a predefined PLCOm2012 model threshold with the categorical NELSON risk criteria.

METHODS: In this ongoing prospective cohort study, current or former smokers aged 55-79 years who met either NELSON risk criteria or had a PLCOm2012 6-year risk of at least 1·58% were recruited from three certified German lung cancer centres in Großhansdorf, Hannover, and Lübeck, and received low-dose CT at baseline and 1-year follow-up screening rounds, including all downstream follow-up procedures. The PLCOm2012 cutoff point of at least 1·58% was predefined and estimated to result in an equal group size as with the NELSON inclusion criteria. The primary outcome was the comparison of the positive predictive values for lung cancers detected in PLCOm2012-selected versus NELSON-selected groups. Here, we report the final results of the primary analysis. This study is registered with ClinicalTrials.gov, NCT04913155.

FINDINGS: Between July 23, 2021, and Aug 19, 2022 (end of recruitment), 5191 participants (2208 [43·5%] female, 2983 [57·5%] male, and 5076 [97·8%] of European White ethnicity) who met either one or both high-risk criteria were enrolled (4167 PLCOm2012-selected vs 3916 NELSON-selected participants) and underwent the baseline low-dose CT scan. In the observation period between the two low-dose CT screening rounds (mean volume CT dose index 1·15 mGy [SD 0·15]) with a median time interval of 1·05 years (IQR 0·95-1·08), 111 lung cancers were detected. The positive predictive value (lung cancer detection rate) in the PLCOm2012-selected group was 108 of 4167 participants (2·59% [95% CI 2·13-3·12]) compared with 85 of 3916 participants (2·17% [1·74-2·68]) in the NELSON-selected group (p=0·0016), resulting in a lower number needed to screen (38·6 [32·1-46·9] vs 46·1 [37·3-57·5]).

INTERPRETATION: Participant selection using the PLCOm2012 risk prediction model with a 6-year risk of at least 1·58% cutoff is more efficient and effective in detecting lung cancer than the NELSON criteria and should therefore be implemented in lung cancer screening programmes.

FUNDING: Federal Ministry of Education and Research (German Center for Lung Research) and AstraZeneca.

PMID: 41232542 [Indexed for MEDLINE]

14. J Nanobiotechnology. 2025 Nov 10;23(1):709. doi: 10.1186/s12951-025-03792-2.

Targeting bone marrow adipocyte-driven fatty acid metabolism to overcome drug resistance in lung cancer bone metastasis.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with bone metastasis presenting a significant challenge due to its association with severe skeletal complications and therapy resistance. This study investigates the role of bone marrow adipocytes (BMAs) in modulating fatty acid metabolism within the bone metastatic niche of lung cancer. Utilizing single-cell sequencing and in vitro co-culture models, we identified critical interactions between BMAs and metastatic lung cancer cells that enhance fatty acid metabolism, promoting tumor survival and drug resistance. To target this metabolic axis, we screened a library of fatty acid synthesis inhibitors, and developed a nanoparticle system encapsulating kaempferol, and cisplatin, surface-modified with poly-aspartic acid for efficient bone targeting. The nanoparticles release their therapeutic payload in the acidic tumor microenvironment, disrupting fatty acid metabolism and overcoming chemoresistance. Our findings highlight the metabolic reprogramming driven by BMAs in bone metastasis and propose a novel therapeutic strategy to improve outcomes for patients with metastatic lung cancer.

PMID: 41214690 [Indexed for MEDLINE]

15. Mol Cancer. 2025 Nov 25;24(1):296. doi: 10.1186/s12943-025-02507-3.

Increased plasma concentrations of acyl-coenzyme A binding protein (ACBP) predict future lung cancer development in smokers at risk of cardiovascular disease.

BACKGROUND: Acyl-coenzyme A binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, is a tissue stress hormone the circulating concentrations of which increase with age, obesity and cardiometabolic risk factors. Elevated plasma ACBP/DBI levels have recently been associated with future cardiovascular and cancer risk, particularly lung cancer (LC), independent of smoking status.

METHODS: To validate ACBP/DBI as a biomarker of LC risk, we analyzed plasma samples from four independent cohorts within the PREVALUNG EU consortium: healthy volunteers, the FLEMENGHO cohort of smokers at cardiovascular risk, the ROBINSCA cohort of smokers at risk of cardiovascular disease (CVD) who later developed LC, and the PREVALUNG cohort of smokers with manifest CVD. ACBP/DBI concentrations were quantified using the Olink proximity extension assay, benchmarked against ELISA and Somascan platforms.

RESULTS: Across cohorts, individuals who subsequently developed LC exhibited higher baseline ACBP/DBI levels than cancer-free controls. In smokers at cardiovascular risk but without manifest CVD, ACBP/DBI discriminated future LC cases with an AUC-ROC of 0.68 (unadjusted) and 0.73 (adjusted for age, sex, BMI and smoking). Elevated ACBP/DBI levels predicted LC occurrence over more than a decade of follow-up. In contrast, among smokers with established CVD, ACBP/DBI levels were uniformly high regardless of cancer outcome.

CONCLUSIONS: These findings independently validate ACBP/DBI as a circulating biomarker of future LC development in at-risk individuals. Clinically, ACBP/DBI quantification could refine risk-adapted lung cancer screening strategies, guiding the frequency of low-dose CT scans and identifying candidates for preventive interventions, including potential ACBP/DBI-neutralizing therapies.

PMID: 41291789 [Indexed for MEDLINE]

16. Adv Sci (Weinh). 2025 Nov;12(44): e08225. doi: 10.1002/advs.202508225. Epub 2025 Sep 3.

Integrin αvβ6-Targeted PET/CT Imaging of Non-Small Cell Lung Cancer with [(68)Ga]Ga-Trivehexin: Improved Preoperative Lymph Node Staging and Association with Immunohistochemistry.

Integrin αvβ6, an epithelial-specific integrin, plays a crucial role in the development and prognosis of multiple tumors and has emerged as a potential target for cancer diagnosis and treatment. The novel integrin αvβ6-targeted radiotracer [68Ga]Ga-Trivehexin shows excellent targeting specificity and favorable tumor-to-background contrast. In this prospective clinical study (NCT05835570) involving 58 participants with non-small cell lung cancer (NSCLC), [68Ga]Ga-Trivehexin and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) showed perfect diagnostic accuracy (100%, 58/58) for the detection of primary tumors. In detecting lymph node metastasis, [68Ga]Ga-Trivehexin exhibited similar diagnostic sensitivity to [18F]FDG PET/CT (80.0% vs 72.0%), with higher specificity (93.8% vs 62.5%, p < 0.001) and accuracy (91.2% vs 64.2%, p < 0.001) in per-station analysis. [68Ga]Ga-Trivehexin outperformed [18F]FDG in detecting brain metastasis (sensitivity, 92.3% vs 38.5%; p = 0.031). Additionally, [68Ga]Ga-Trivehexin PET/CT results changed the therapeutic regimens of 14 (24.1%) participants. The maximum standardized uptake value (SUVmax) and tumor-to-liver parenchyma ratio (TLR) derived from [68Ga]Ga-Trivehexin correlated with integrin β6 expression in NSCLC. Overall, [68Ga]Ga-Trivehexin PET/CT represents an invaluable tool for identifying lymph node and brain metastases and shows comparable diagnostic efficacy in detecting primary tumors and other distant metastases compared with [18F]FDG in NSCLC, potentially guiding treatment decision-making.

PMID: 40899568 [Indexed for MEDLINE]

17. Nat Commun. 2025 Nov 11;16(1):9915. doi: 10.1038/s41467-025-64862-5.

A monoclonal antibody that inhibits the shedding of CD16a and CD16b and promotes antibody-dependent cellular cytotoxicity against tumors.

CD16a triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis by natural killer (NK) cells and macrophages in anti-tumor immunity. However, CD16a undergoes cleavage by ADAM17 that dampens its anti-tumor immunity. We here develop a monoclonal antibody (F9H4) that binds to CD16a and inhibits its cleavage. F9H4 retains CD16a on the surface of NK cells and macrophages, without triggering or blocking CD16a. F9H4 also binds to and inhibits shedding of CD16b by neutrophils, and inhibits CD16a/b shedding by leukocytes in tumor samples from lung cancer patients. F9H4 promotes ADCC against lung cancer cells that are opsonized by cetuximab, an epidermal growth factor receptor antibody that engages CD16a. F9H4 synergizes with cetuximab to inhibit human lung adenocarcinoma development in immunodeficient mice reconstituted with human NK cells. F9H4 combining with cetuximab also inhibits murine lung carcinoma growth in Fc gamma receptor-humanized mice, and such effect is mediated by NK cells and macrophages. The efficacy of F9H4+cetuximab in lung cancer models is the proof-of-concept for this new approach that promotes anti-tumor functions of Fc-enabled antibodies.

PMID: 41219228 [Indexed for MEDLINE]

18. Adv Sci (Weinh). 2025 Nov;12(43): e09604. doi: 10.1002/advs.202509604. Epub 2025 Oct 3.

Intravenous iRGD-Guided, RBC-Membrane Camouflaged Lactococcus Lactis Remodels Cold NSCLC and Enhances PD-1 Blockade.

Resistance to programmed-death-1/programmed-death-ligand-1 (PD-1/PD-L1) blockade in non-small-cell lung cancer (NSCLC) arises mainly from weak tumor immunogenicity and limited effector T-cell infiltration. Here, this work presents an intravenously deliverable "living medicine" that addresses these barriers through biomimetic cloaking, tumor-penetrating guidance, and synthetic-biology-driven cytokine release. Lactococcus lactis is engineered to co-secrete Flt3L and OX40L (FOLactis) and then camouflage with red-blood-cell membranes, producing long-circulating mRBC@FOLactis. Conjugation of the iRGD peptide (iRGD-mRBC@FOLactis) enables trans-endothelial migration and deep (≥200 µm) interstitial penetration, yielding a fourfold increase in intratumorally bacterial accumulation versus unmodified FOLactis. In the orthotopic Lewis lung carcinoma (LLC) model, a single intravenous dose of iRGD-mRBC@FOLactis combined with anti-PD-1 antibody achieves complete tumor regression in 60% of mice, doubles median survival (p < 0.001), and generates systemic tumor-specific immune memory. Mechanistically, local Flt3L and OX40L secretion expands cross-presenting dendritic cells (DCs), boosts CD8⁺ T-cell priming, and converts immunologically "cold" tumors into inflamed, T-cell-rich lesions, thereby overcoming primary resistance to checkpoint blockade. This multifunctional probiotic platform establishes a generalizable strategy for systemic delivery of living therapeutics and offers a powerful adjunct to PD-1/PD-L1 blockade for NSCLC and other treatment-resistant solid tumors.

PMID: 41042114 [Indexed for MEDLINE]

19. Eur Respir J. 2025 Nov 13;66(5):2500156. doi: 10.1183/13993003.00156-2025. Print 2025 Nov.

European Respiratory Society and European Society of Thoracic Surgeons clinical practice guideline on fitness for curative intent treatment of lung cancer.

A multidisciplinary panel of lung cancer experts with a special interest in functional evaluation of lung cancer patients, and lung cancer patient representatives, has been facilitated by the European Society of Thoracic Surgeons and the European Respiratory Society to provide healthcare professionals with practical and up-to-date recommendations for the assessment of patients' fitness for curative intent treatments for lung cancer. The panel formulated four PICO (population, intervention, comparison and outcomes) questions and seven complementary narrative questions. Both types of questions were assigned to groups of at least two experts. A medical librarian conducted the literature searches, and the authors selected relevant studies based on predefined inclusion criteria. Risk of bias was assessed using the QUIPS (Quality in Prognosis Studies) tool. Data were summarised and the certainty of evidence was assessed with GRADE (Grading of Recommendations, Assessment, Development and Evaluations) and the Evidence to Decisions framework was used to formulate recommendations. A series of multidisciplinary recommendations was formulated about the utilisation of pulmonary function tests, split lung function values, exercise tests, cardiologic testing, and the role of prehabilitation, sublobar resections, risk scores and comorbidities in selecting patients for curative intent treatment.

PMID: 41232938 [Indexed for MEDLINE]

20. J Clin Invest. 2025 Nov 3;135(21): e198802. doi: 10.1172/JCI198802. eCollection 2025 Nov 3.

TET3-overexpressing macrophages are a unifying pathogenic feature with therapeutic potential in chronic inflammatory diseases.

Comment on

    TET3 is a common epigenetic immunomodulator of pathogenic macrophages.

Increased activation of the NLRP3 inflammasome in immune cells, including macrophages, has been implicated in the pathogenesis of multiple chronic inflammatory diseases. Targeted depletion of macrophages has been explored as a cross-disease therapeutic strategy, but without subtype-specific markers, this strategy risks elimination of macrophages with homeostatic functions. In this study, Liu et al. identified a subpopulation of pathogenic macrophages, referred to as Toe-Macs, which are characterized by overexpression of the DNA demethylase TET3 in metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. When induced into the disease microenvironment, Toe-Macs produced proinflammatory cytokines and chemokines. Selective elimination of Toe-Macs attenuated disease progression without any discernible side effects in mouse models of MASH and NSCLC. These findings highlight the role of Toe-Macs in the pathogenesis of chronic inflammatory diseases and provide a rationale for exploring TET3 as a therapeutic target.

PMID: 41178715 [Indexed for MEDLINE]

21. J Am Chem Soc. 2025 Nov 5;147(44):40664-40675. doi: 10.1021/jacs.5c12860. Epub 2025 Oct 23.

Personalized Cancer-Specific Protein-Aptamer Corona for Orthogonal Multiplex Cancer Diagnosis.

Aptamers are powerful synthetic recognition elements for biosensing, yet their application in complex biofluids, such as human serum, is critically limited by enzymatic degradation. To overcome this fundamental challenge, we introduce a novel analytical platform centered on the concept of a personalized protein-aptamer corona (PAC). This strategy leverages the spontaneous formation of a disease-specific protein corona on magnetic nanoparticles, which not only enriches low-abundance biomarkers but also creates a stabilized, nuclease-free nanobio interface for subsequent aptamer recognition. The integration of this PAC concept with an 8-channel orthogonal multiplexed electrochemical (OMEC) chip enables sensitive, amplification-free (PCR-free) signal transduction via alternating current voltammetry. By coupling this platform with machine learning algorithms, we translate complex, multiplexed aptamer binding signatures into a robust diagnostic output. Clinical validation on two independent cancer cohorts demonstrated outstanding performance, achieving an area under the curve of 99.50% for ovarian cancer (n = 121) and 96.54% for non-small cell lung cancer (n = 107). This work establishes the PAC-OMEC platform as a versatile and powerful strategy for high-throughput clinical diagnostics, fundamentally addressing the instability of aptamers in native biological samples.

PMID: 41129741 [Indexed for MEDLINE]

22. J Am Chem Soc. 2025 Nov 5;147(44):40751-40762. doi: 10.1021/jacs.5c13695. Epub 2025 Oct 23.

Development of Dual-Receptor Lysosome-Targeting Chimeras for Protein Degradation.

A growing array of lysosome-targeting chimeras (LYTACs) have recently emerged as therapeutic candidates to treat malignancies and other diseases via targeted protein degradation. We established a novel dual lysosome-targeting receptor-dependent protein degradation strategy that leverages the synergistic actions of the C-X-C chemokine receptor 4 (CXCR4) and folate receptor 1 (FOLR1) to degrade extracellular and membrane proteins. Using this strategy, we developed dual-receptor lysosome-targeting chimeras to achieve efficient lysosomal degradation of programmed cell death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR). The EGFR chimera inhibited the growth of transplanted T790M-mutated drug-resistant EGFR-driven lung cancer tumors by degrading EGFR. This dual-targeting strategy exhibits significantly better protein degradation capabilities compared with single lysosome-targeting chimeras, providing a novel platform for developing drugs targeting cancer.

PMID: 41127901 [Indexed for MEDLINE]

23. Nat Commun. 2025 Nov 19;16(1):10132. doi: 10.1038/s41467-025-65075-6.

A multiplexed assay by self-assembled dual-target responsive DNA hydrogels for efficacy evaluation of immunotherapy.

Immunotherapy has revolutionized cancer treatment, yet its efficacy is limited to a specific patient subset. This underscores the critical clinical demand for accessible assays capable of assessing immunotherapy outcomes and enabling timely adjustments to personalized medical care. Here, we present a multiplexed assay based on dual-target responsive DNA hydrogels for the simultaneous detection of soluble programmed death-ligand 1 and lactate dehydrogenase in lung cancer patients. The DNA hydrogel, constructed through a self-assembly strategy, achieves superior performance by reducing background noise by 33.8% and improving the signal-to-noise ratio by 61.5%. By integrating rolling circle amplification, the assay enables ultrasensitive detection at femtomolar levels. When further combining additional clinical biomarkers, the assay demonstrates strong predictive ability for immunotherapy response, achieving an area under the curve value of 0.935 in clinical cohort. Collectively, this blood-based assay offers a versatile and effective approach for advancing biomarker-based evaluations of immunotherapy outcomes.

PMID: 41258095 [Indexed for MEDLINE]

24. Mol Cancer. 2025 Nov 20;24(1):294. doi: 10.1186/s12943-025-02425-4.

Long non-coding RNA AFAP1-AS1 promotes alternative splicing of AXIN2 by facilitating SRSFs phase separation to induce drug resistance in lung adenocarcinoma.

Lung cancer currently holds the highest global incidence and mortality rates among malignant tumors, with lung adenocarcinoma being the most prevalent and deadly subtype. Chemotherapy and targeted therapy remain the standard treatments for lung adenocarcinoma, but tumor resistance continues to be a significant clinical challenge. In this study, we identified that the long non-coding RNA actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1), which is highly expressed in lung adenocarcinoma, regulates RNA alternative splicing by recruiting splicing factors such as serine and arginine rich splicing factor 1 and 3 (SRSF1 and SRSF3), promoting their liquid-liquid phase separation. Among the affected splicing events, the exon 7 skipping of the key regulatory gene AXIN2, involved in the Wnt/β-catenin signaling pathway, is most notably regulated by AFAP1-AS1, resulting in the translation of a truncated AXIN2 isoform (AXIN2-S). This isoform facilitates the accumulation of β-catenin in the nucleus and the persistent activation of Wnt/β-catenin signaling pathway, ultimately contributing to drug resistance in lung adenocarcinoma. Our work uncovers a novel function of AFAP1-AS1 in regulating RNA alternative splicing through the modulation of splicing factors phase separation. This mechanism highlights an unrecognized pathway by which AFAP1-AS1 promotes drug resistance in lung adenocarcinoma, suggesting that AFAP1-AS1 and its regulated splicing events may serve as potential biomarkers or therapeutic targets for the treatment of lung adenocarcinoma.

PMID: 41261425 [Indexed for MEDLINE]

25. J Clin Invest. 2025 Aug 12;135(21): e194879. doi: 10.1172/JCI194879. eCollection 2025 Nov 3.

TET3 is a common epigenetic immunomodulator of pathogenic macrophages.

Comment in

    TET3-overexpressing macrophages are a unifying pathogenic feature with therapeutic potential in chronic inflammatory diseases.

Through a combination of single-cell/single-nucleus RNA-Seq (sc/snRNA-Seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by Tet methylcytosine dioxygenase 3 (TET3) overexpression (Toe-Macs) in 3 major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enabled their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 KO markedly mitigated disease progression, and the therapeutic effects were recapitulated pharmacologically using a TET3-specific small-molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulated the expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.

PMID: 40794443 [Indexed for MEDLINE]

26. Nat Commun. 2025 Nov 6;16(1):9754. doi: 10.1038/s41467-025-64821-0.

Mutation of CMTR2 in Lung Adenocarcinoma Alters RNA Alternative Splicing and Reveals Therapeutic Vulnerabilities.

RNA splicing dysregulation has emerged as a hallmark of cancer and a promising therapeutic target; however, its full landscape in human solid cancer remains poorly characterized. To address this, we perform alternative splicing analyses using RNA-sequencing data from 751 lung adenocarcinoma samples from our cohort integrated with 519 samples from The Cancer Genome Atlas. Visualization of splicing patterns using t-distributed stochastic neighbor embedding reveals substantial inter-tumor heterogeneity driven by distinct molecular subtypes and histological differentiation. We identify a unique molecular subtype associated with inactivating mutations in CMTR2, which encodes Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 2. CMTR2 mutations are observed in 3.8% of cases and are predominantly truncating mutations, which form an isolated cluster within the splicing landscape. Intrinsic and CRISPR-Cas9-engineered CMTR2 mutations disrupt alternative splicing and sensitize cancer cells to sulfonamide-based RNA splicing modulators and immune checkpoint blockade therapy. Retrospective patient data confirm the increased sensitivity of CMTR2-deficient tumors to immune checkpoint blockade therapy. These findings uncover a previously unrecognized RNA splicing deficiency in human cancers and define a molecular subtype of lung adenocarcinoma driven by RNA splicing dysregulation, suggesting targets for therapeutic intervention in lung cancer.

PMID: 41198678 [Indexed for MEDLINE]

27. Nat Rev Clin Oncol. 2025 Nov;22(11):806-830. doi: 10.1038/s41571-025-01061-7. Epub 2025 Aug 14.

Treatment of NSCLC after chemoimmunotherapy - are we making headway?

The treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway. Consequently, current strategies designed to overcome resistance aim to restore antitumour immunity via antibody-based therapies (including bispecific antibodies, T cell engagers and antibody-drug conjugates), targeted therapies, adoptive cell therapies, therapeutic vaccines or intratumoural immunotherapies. Although substantial progress has been made in identifying potential biomarkers associated with immune resistance, the clinical relevance of many of these observations remains limited. Biomarker-driven studies using adaptive, hypothesis-generating designs might offer a promising path forward by navigating the complexity of resistance and enabling the timely evaluation of novel therapeutic concepts. In this Review, we summarize the latest advances in addressing resistance to ICIs in patients with advanced-stage NSCLC and provide insights into emerging clinical strategies and future research directions.

PMID: 40813911 [Indexed for MEDLINE]

28. J Adv Res. 2025 Nov;77:733-746. doi: 10.1016/j.jare.2025.01.028. Epub 2025 Jan 18.

A novel small molecule NJH-13 induces pyroptosis via the Ca (2+) driven AKT-FOXO1-GSDME signaling pathway in NSCLC by targeting TRPV5.

INTRODUCTION: Pyroptosis represents a mode of programmed necrotic cell death (PCD), mediated by members of gasdermin family (GSDMs), such as GSDME. It is emerging as a promising approach for combating cancer. Notably, GSDME is the key modulator for the switch between apoptosis and pyroptosis in cells. However, GSDME is often downregulated in many malignancies, including lung adenocarcinoma.

OBJECTIVE: To identify novel pyroptosis inducers in non-small cell lung cancer (NSCLC) and dissect the underlying mechanism.

METHODS: Pyroptosis was examined by live cell imaging, PI/Hoechst/Annexin V staining, LDH release assay, ELISA, and western blot assays. DARTS, CETSA, molecular docking was used to identify the target of NJH-13. RNA-seq, qPCR, chromatin immunoprecipitation (ChIP), dual luciferase assays were used elucidate the mechanism.

RESULTS: In this study, NJH-13, an N-containing heterocycle, was screened out and identified to possess the ability to activate GSDME, consequently triggering pyroptosis in NSCLC cells. By using the DARTS strategy, transient receptor potential cation channel subfamily V member 5 (TRPV5) was identified as a potential target of NJH-13. NJH-13 increased intracellular calcium level and triggered oxidative stress, both of which are critical events leading to pyroptosis mediated by GSDME. Mechanistically, NJH-13 enhanced the transcription of GSDME via the protein kinase B (AKT)/forkhead box transcription factor O1 (FOXO1) signaling pathway. ChIP revealed that FOXO1 bound directly to the promoter region of GSDME, thus triggering the GSDME-mediated pyroptosis. Pharmacological and genetic activation of AKT or inhibition of FOXO1 partially rescued NJH-13-induced pyroptotic cell death. Moreover, NJH-13 treatment suppressed tumor growth in vivo.

CONCLUSION: Taken together, our results revealed that TRPV5 is a distinctive target for manipulating pyroptosis and provided evidence that NJH-13 functions as a potential anti-cancer agent capable of triggering pyroptosis in NSCLC cells.

PMID: 39832720 [Indexed for MEDLINE]

29. Cancer Discov. 2025 Nov 3;15(11):2235-2250. doi: 10.1158/2159-8290.CD-24-1515.

Eradicating Drug-tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy.

EGFR tyrosine kinase inhibitors have dramatically improved outcomes for patients with EGFR-mutated non-small cell lung cancer (NSCLC), but relapse frequently occurs because of drug-tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody-drug conjugates (ADC). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo. Treatment with the TROP2 ADC sacituzumab govitecan at the time of osimertinib-induced minimal residual disease only modestly delayed tumor recurrence in vivo, whereas a single infusion of sacituzumab-based TROP2-directed chimeric antigen receptor (CAR) T cells significantly prolonged relapse-free survival, with evidence of cure. These data highlight the potential of engineering TROP2 CAR T-cell therapy to eliminate EGFR DTPs in patients.

SIGNIFICANCE: We provide a rationale for targeting TROP2 in EGFR-mutated NSCLC DTPs. In contrast to TROP2 ADC therapy, targeting of TROP2 with CAR-T cells can eliminate osimertinib-induced DTPs in vivo, revealing the promise of developing novel TROP2-based CAR-T cells to promote durable response and prevent disease relapse in patients.

PMID: 40762432 [Indexed for MEDLINE]

30. Signal Transduct Target Ther. 2025 Nov 28;10(1):389. doi: 10.1038/s41392-025-02482-7.

MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer.

Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with MET amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.

PMID: 41309558 [Indexed for MEDLINE]

31. J Thorac Oncol. 2025 Nov;20(11):1594-1614. doi: 10.1016/j.jtho.2025.07.009. Epub 2025 Jul 7.

Molecular Tumor Boards: A Consensus Statement From the International Association for the Study of Lung Cancer.

CONTEXT: Molecular tumor boards (MTBs) are multidisciplinary meetings of specialists dedicated to analyzing biomarker test results to provide personalized treatment recommendations. However, global disparities in the successful implementation of MTBs exist, driven by unequal access to molecular diagnostics and supportive multidimensional expertise.

OBJECTIVE: To establish recommendations for MTB implementation, outline practical frameworks for their operation, and address disparities in expertise and resources between new and established MTBs.

DESIGN: A modified Delphi method involved 37 international experts in three survey rounds and online meetings, with consensus defined as more than or equal to 75% agreement.

RESULTS: The panel identified a molecular biologist or pathologist with expertise in molecular diagnostics and tumor-specific medical oncologists as indispensable MTB members. Case selection should reflect institutional expertise and volume, with newer MTBs reviewing less selected cases to gain experience. Regular meetings are advised to avoid delays beyond 14 days from result availability to discussion. Reporting should be standardized to include clinicopathologic data (tumor characteristics, treatment history), biomarker findings (testing results, sample details), and recommendations (treatment, retesting, genetic counseling). Treatment options should be ranked by the level of evidence for actionability and may include options not available locally. Performance evaluation should consider changes in patient management based on MTB input and matched therapy rates.

CONCLUSIONS: These MTB consensus recommendations are applicable across tumor types, despite being developed by lung cancer and molecular specialists and initiated by the International Association for the Study of Lung Cancer. They provide a structured framework for MTB implementation, report standardization, case selection, and quality assessment, aiming to standardize practice and address gaps in expertise for personalized cancer care.

PMID: 40633839 [Indexed for MEDLINE]

32. Signal Transduct Target Ther. 2025 Nov 11;10(1):365. doi: 10.1038/s41392-025-02460-z.

Ablation plus immunotherapy versus immunotherapy alone in patients of advanced NSCLC who develop oligo-residual disease after anti-PD-1/L1 therapy (BOOSTER): a randomized phase 2 trial.

Local consolidative therapy (LCT) has been demonstrated to enhance the survival benefits of immunotherapy in non-small cell lung cancer (NSCLC) patients with oligometastatic or oligoprogressive disease. This randomized, phase 2 trial investigated the efficacy and safety of ablation combining continuous immunotherapy in NSCLC patients with oligo-residual disease (ORD) after anti-PD-1/L1 therapy (ChiCTR, identifier: ChiCTR2000032479). From March 2021 to March 2024, 65 patients were randomly assigned (2:1) to ablation combination group (n = 43) and immunotherapy maintenance group (n = 22), and the full analysis set finally included 42 patients in ablation plus immunotherapy group and 20 patients in immunotherapy maintenance group. With a median follow-up duration of 17.8 months, patients receiving ablation combination were associated with significantly longer PFS (median 26.7 vs. 11.7 months, p < 0.001, HR = 0.213, 95%CI 0.099-0.461) and a trend of longer OS (p = 0.036, HR = 0.242, 95%CI 0.057-1.019) than those without ablation. Subgroup analysis showed that cryoablation (n = 13) yielded potentially superior survival than thermal ablation (n = 31) (mPFS: NA vs. 22.4 months, p = 0.011), which might induced by the elevated level of IFN-α after cryotherapy compared to thermal ablation (p = 0.078). Additionally, ablation combination group showed a decreased rate of systemic progression pattern compared with immunotherapy maintenance group. Regarding safety, the combination of ablation and immunotherapy was well tolerated, with only 1 patient experiencing grade 3 pneumothorax after ablation. In conclusion, the addition of ablation is well-tolerated and prolongs the survival of immunotherapy in patients with advanced NSCLC who develop ORD after anti-PD-1/L1 therapy, while cryoablation showing potentially superior survival benefit compared to thermal ablation.

PMID: 41213939 [Indexed for MEDLINE]

33. Nat Med. 2025 Nov;31(11):3654-3661. doi: 10.1038/s41591-025-03883-5. Epub 2025 Aug 19.

First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial.

Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody-drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5 mg kg-1, every 3 weeks) plus tagitanlimab (1,200 mg, every 3 weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5 mg kg-1, every 2 weeks) plus tagitanlimab (900 mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63 years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ≥3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3 months for cohort 1A and 13.0 months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4 months (95% confidence interval 6.7-17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration: NCT05351788 .

PMID: 40830660 [Indexed for MEDLINE]

34. Nature. 2025 Nov;647(8088):257-267. doi: 10.1038/s41586-025-09503-z. Epub 2025 Sep 17.

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.

Update of

    bioRxiv. 2024 Nov 15:2024.11.13.623500. doi: 10.1101/2024.11.13.623500.

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1-9. The mechanisms driving neuroendocrine-tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10-13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity, offering new insights for targeting lineage plasticity.

PMID: 40963028 [Indexed for MEDLINE]

35. Nat Commun. 2025 Nov 14;16(1):10022. doi: 10.1038/s41467-025-66170-4.

scFFPE-ATAC enables high-throughput single cell chromatin accessibility profiling in formalin-fixed paraffin-embedded samples.

Formalin-fixed paraffin-embedded (FFPE) samples are the gold standard for tissue preservation in clinical and research settings. Current single-cell chromatin accessibility technologies cannot resolve cell-type-specific epigenetic profiles in FFPE tissues due to extensive DNA damage. We present scFFPE-ATAC, a high-throughput single-cell chromatin accessibility assay for FFPE samples that integrates an FFPE-adapted Tn5 transposase, ultra-high-throughput DNA barcoding (>56 million barcodes per run), T7 promoter-mediated DNA damage repair, and in vitro transcription. We benchmark scFFPE-ATAC on FFPE mouse spleen and validate its performance against fresh tissue. We apply it to human lymph node samples archived for 8-12 years and to lung cancer FFPE tissues, revealing distinct regulatory trajectories between tumor center and invasive edge. Analysis of archived follicular lymphoma and transformed diffuse large B-cell lymphoma samples identifies relapse- and transformation-associated epigenetic dynamics. scFFPE-ATAC enables retrospective, spatial, and mechanistic epigenetic studies in long-term archived specimens.

PMID: 41238550 [Indexed for MEDLINE]

36. J Clin Oncol. 2025 Nov 10;43(32):3516-3525. doi: 10.1200/JCO-25-00221. Epub 2025 Aug 11.

Hippocampal Avoidance During Prophylactic Cranial Irradiation for Patients With Small Cell Lung Cancer: Randomized Phase II/III Trial NRG-CC003.

PURPOSE: Hippocampal avoidance (HA) during therapeutic whole-brain radiotherapy reduces the risk of neurocognitive function (NCF) toxicity in patients with brain metastasis. This trial hypothesized that HA during prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) leads to noninferior intracranial relapse (ICR) and reduction in NCF toxicity.

METHODS: This randomized phase II/III trial enrolled patients with SCLC, no brain metastases, and response to chemotherapy. The primary end points were 12-month ICR (noninferiority design, randomized phase II) and 6-month Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure (phase III). Secondary end points were failure in any NCF test, health-related quality of life (HRQOL), overall survival (OS), and toxicity.

RESULTS: From December 2015 to June 2022, 393 patients were randomly assigned. The median age was 64 years. Stage and memantine usage were balanced. The median follow-up was 17.0 months (all patients) and 30.8 months (alive patients). HA-PCI had noninferior 12-month ICR rate (PCI 14.8% v HA-PCI 14.7%, P < .0001). Six-month HVLT-R DR deterioration was not significantly different (PCI 30.0% v HA-PCI 25.5%, P = .28). Addition of HA to PCI reduced the risk of failure in any NCF test (adjusted hazard ratio [HR], 0.78; 95% CI [0.61 to 0.99]; P = .039). Addition of HA to PCI was not associated with longitudinal change in any HRQOL domain. There were no differences in OS (adjusted HR, 0.88 [95% CI, 0.67 to 1.14]; P = .33) or grade ≥3 toxicity (PCI 31.4% v HA-PCI 30.7%, P = .88).

CONCLUSION: Although the study did not meet its primary end point of DR preservation, HA during PCI reduces the risk of overall neurocognitive toxicity with noninferior ICR risk and similar survival.

PMID: 40789106 [Indexed for MEDLINE]

37. J Clin Oncol. 2025 Nov 20;43(33):3610-3621. doi: 10.1200/JCO-25-00036. Epub 2025 Oct 13.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small Cell Lung Cancer: The Phase III PACIFIC-2 Study.

PURPOSE: Immunotherapy targeting PD-L1 improves outcomes in patients with unresectable stage III non-small cell lung cancer (NSCLC) and no progression after definitive, concurrent chemoradiotherapy (cCRT). Earlier administration of immunotherapy, simultaneously with cCRT, may improve outcomes further.

METHODS: Eligible patients were randomly assigned (2:1) to receive either durvalumab or placebo administered from the start of cCRT. Patients without progression after completing cCRT received consolidation durvalumab or placebo (per initial random assignment) until progression. The primary end point was progression-free survival (PFS) by blinded independent central review. Key secondary end points included objective response rate (ORR), overall survival (OS), the proportion of patients alive at 24 months (OS24), and safety.

RESULTS: In total, 328 patients were randomly assigned to receive durvalumab (n = 219) or placebo (n = 109). There was no statistically significant difference with durvalumab versus placebo in PFS (hazard ratio [HR], 0.85 [95% CI, 0.65 to 1.12]; P = .247) or OS (HR, 1.03 [95% CI, 0.78 to 1.39]; P = .823); OS24 was 58.4% versus 59.5%, respectively. Confirmed ORR was 60.7% with durvalumab versus 60.6% with placebo (difference, 0.2% [95% CI, -15.2 to 16.3%]; P = .976). With durvalumab versus placebo, respectively, maximum grade 3 or 4 adverse events (AEs) occurred in 53.4% versus 59.3% of patients, pneumonitis or radiation pneumonitis (group term) in 28.8% (grade ≥3: 4.6%) versus 28.7% (grade ≥3: 5.6%), AEs leading to discontinuation of durvalumab or placebo in 25.6% versus 12.0%, and fatal AEs in 13.7% versus 10.2%.

CONCLUSION: Among patients with unresectable stage III NSCLC, durvalumab administered from the start of cCRT failed to demonstrate additional benefit compared with cCRT plus placebo. Consolidation durvalumab following definitive cCRT remains the standard of care in this setting.

PMID: 41082707 [Indexed for MEDLINE]

38. Lancet Oncol. 2025 Nov;26(11):1454-1466. doi: 10.1016/S1470-2045(25)00465-6.

Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a novel antibody-drug conjugate targeting HER3, which is overexpressed in CNS metastases of advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the activity and safety of HER3-DXd in patients with advanced NSCLC and newly diagnosed brain metastases or brain metastases progressing after local therapy.

METHODS: TUXEDO-3 is a multicohort, multicentre, open-label, single-arm phase 2 trial. In this cohort (2 of 3), we enrolled adults (aged ≥18 years) with histologically documented squamous or non-squamous NSCLC, radiologically documented metastatic disease, newly diagnosed brain metastases or progressing brain metastases after local treatment, at least one brain lesion, no need for immediate local therapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received HER3-DXd 5·6 mg/kg intravenously once every 3 weeks. The threshold to meet the primary endpoint was at least 15% of patients having an intracranial response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. Activity and safety analyses were done in the full analysis set, which included all participants who received at least one dose of HER3-DXd. This trial (ClinicalTrials.govNCT05865990 and European Union Clinical Trials Register 2023-503251-10-00) is ongoing but no longer enrolling patients.

FINDINGS: Between Dec 27, 2023, and Sept 6, 2024, 20 patients were recruited; ten (50%) were female and ten (50%) were male. 16 (80%) of 20 patients were White; race was not reported in the remaining four patients. 13 (65%) of the 20 patients had brain metastases progressing after local therapy and seven (35%) had untreated brain metastases; five (25%) had activating driver mutations. Median follow-up was 5·3 months (IQR 2·0-8·5). The primary endpoint was met, with six (30%) of 20 patients having intracranial responses (objective response rate 30·0%, 95% CI 11·9-54·3). The six responders had non-squamous advanced NSCLC (two [33%] with untreated brain metastases and four [67%] with progressing brain metastases), of whom one (17%) had an activating driver mutation (KRAS G12C). Treatment-related adverse events occurred in 16 (80%) patients, the most common of which were nausea (seven [35%] patients), and diarrhoea and asthenia (each six [30%] patients). The most common grade 3 and 4 adverse events were neutropenia in three (15%) patients and febrile neutropenia in two (10%). There were no treatment-related deaths, and no new safety signals were identified.

INTERPRETATION: HER3-DXd showed promising clinical activity in patients with advanced NSCLC and active brain metastases, and could represent a novel treatment option in this setting.

FUNDING: Daiichi-Sankyo and Merck Sharp & Dohme.

PMID: 41167214 [Indexed for MEDLINE]

39. Lancet Oncol. 2025 Nov;26(11):1432-1442. doi: 10.1016/S1470-2045(25)00462-0.

Epub 2025 Oct 11.

Radiotherapy-free pembrolizumab combined with chemotherapy for locally advanced non-small-cell lung cancer with PD-L1 tumour proportion score of 50% or higher (Evolution trial): a multicentre, single-arm, phase 2 study.

BACKGROUND: The standard of care for unresectable, locally advanced non-small-cell lung cancer (NSCLC) is chemoradiotherapy followed by durvalumab. This study (Evolution trial WJOG11819L) aimed to evaluate the efficacy and safety of radiotherapy-free pembrolizumab and chemotherapy in patients with unresectable, locally advanced NSCLC with a PD-L1 tumour proportion score (TPS) of 50% or higher.

METHODS: This prospective, multicentre, single-arm, phase 2 study was conducted in nine institutes in Japan. Inclusion criteria were age 20 years or older, histologically confirmed unresectable, locally advanced NSCLC with a PD-L1 TPS of 50% or higher, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, no previous systemic therapy, and adequate organ function. Patients received intravenous induction therapy comprising pembrolizumab 200 mg every 3 weeks plus platinum-based chemotherapy for four cycles: either cisplatin 75 mg/m2 or carboplatin (area under the curve [AUC] 5 for non-squamous NSCLC, AUC 6 for squamous NSCLC) plus pemetrexed 500 mg/m2 (non-squamous NSCLC) or nanoparticle albumin-bound paclitaxel 100 mg/m2 on days 1, 8, and 15 (squamous NSCLC). This was followed by maintenance therapy comprising intravenous pembrolizumab (200 mg) with or without intravenous pemetrexed (500 mg/m2) every 3 weeks for up to 2 years. The primary endpoint was 2-year progression-free survival and was assessed in the full analysis set (ie, all patients who met the eligibility criteria and received at least one dose of study treatment). The safety analysis set included all patients who received at least one dose of study treatment and had at least one post-treatment safety assessment. This trial was registered with ClinicalTrials.gov (NCT04153734) and is complete.

FINDINGS: Between May 18, 2020, and Feb 22, 2022, 21 patients were assessed for eligibility and all were enrolled. Median age was 73 years (IQR 68-80); 16 (76%) patients were male; race and ethnicity data were not collected. Three (14%) patients discontinued and 18 (86%) patients completed the induction therapy; eight (38%) patients discontinued during maintenance therapy and ten (48%) patients completed the maintenance therapy. Median follow-up was 32·5 months (IQR 26·2-39·5). The 2-year progression-free survival rate was 67% (90% CI 46-83). The most common grade 3 or worse adverse events were neutropenia (eight [38%] of 21 patients), leukopenia (four [19%]), and pneumonia (three [14%]). Serious adverse events occurred in seven (33%) patients. No treatment-related deaths were reported.

INTERPRETATION: These findings suggest that pembrolizumab combined with platinum-based chemotherapy, without radiotherapy, might provide a feasible and promising alternative treatment strategy for patients with unresectable, locally advanced NSCLC with a PD-L1 TPS of 50% or higher.

FUNDING: Merck Sharp & Dohme.

PMID: 41082893 [Indexed for MEDLINE]

40. Nat Rev Clin Oncol. 2026 Jan;23(1):63-83. doi: 10.1038/s41571-025-01085-z. Epub 2025 Nov 11.

Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC - mechanisms and evolving treatment approaches.

Resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major obstacle in the clinical management of EGFR-mutant non-small-cell lung cancer (NSCLC). Despite the transformative therapeutic activity of the multiple iterations of EGFR TKIs, spanning from first-generation reversible inhibitors such as erlotinib and gefitinib to the current standard-of-care third-generation covalent inhibitor osimertinib, primary or acquired resistance to these agents inevitably emerges via diverse mechanisms. The advent of combination therapies that incorporate chemotherapy, anti-angiogenic agents, bispecific antibodies or antibody-drug conjugates has increased clinical benefit but introduced new resistance phenotypes, underscoring the dynamic plasticity and complexity of tumour evolution under therapeutic pressure. In this Review, we provide a comprehensive synthesis of the molecular mechanisms that underlie resistance to third-generation EGFR TKIs, describe biomarker-guided and biomarker-unselected therapeutic strategies to overcome these mechanisms, and discuss emerging approaches to pre-empt resistance through early application of combination therapies. We highlight the paradigm shift from radiological to molecular monitoring of resistance to therapy and explore how advances in circulating tumour DNA analysis, artificial intelligence and multi-omics might facilitate adaptive treatment strategies. As the therapeutic landscape evolves, a more complete mechanistic understanding of resistance will be essential to guide rational treatment sequencing, inform trial design and improve long-term outcomes for patients with EGFR-mutant NSCLC.

PMID: 41219394 [Indexed for MEDLINE]

41. Cancer Res. 2025 Nov 14;85(22):4341-4358. doi: 10.1158/0008-5472.CAN-24-3360.

Metastasis-Initiating Osteosarcoma Subpopulations Establish Paracrine Interactions with Lung and Tumor Cells to Create a Metastatic Niche.

Osteosarcoma is an aggressive and deadly bone tumor, primarily afflicting children, adolescents, and young adults. Poor outcomes for patients with osteosarcoma are intricately linked with the development of lung metastasis, which is responsible for nearly all deaths caused by osteosarcoma. Identification of the underlying cellular and molecular mechanisms that govern the metastatic colonization of circulating tumor cells to the lung is needed to develop biologically defined, metastasis-targeting therapies. In this study, using a combination of an in vitro organotypic metastasis model, single-cell RNA sequencing, human xenograft models, and murine immunocompetent osteosarcoma models, we found that metastasis is initiated by a subpopulation of hypoproliferative cells with the unique capacity to sustain the production of metastasis-promoting cytokines, such as IL6 and CXCL8, in response to lung epithelial cell-derived IL1α. Critically, genomic and pharmacologic disruption of IL1 signaling in osteosarcoma cells significantly reduced metastatic progression. Collectively, this study shows that tumor-stromal interactions are important for metastasis and suggests that metastatic competency is driven in part by the ability of tumor cells to respond to cues from the metastatic niche. Disruption of tumor-stromal signaling is a promising therapeutic approach to interrupt metastasis progression.

SIGNIFICANCE: Elucidation of key traits of metastasis-competent cancer cells identified cross-talk between osteosarcoma and lung epithelial cells that mediates metastasis and revealed IL1 inhibition as a promising therapeutic strategy for blocking metastasis.

PMID: 40882022 [Indexed for MEDLINE]

42. Adv Mater. 2025 Nov;37(47): e05208. doi: 10.1002/adma.202505208. Epub 2025 Aug 21.

MUTE-Seq: An Ultrasensitive Method for Detecting Low-Frequency Mutations in cfDNA With Engineered Advanced-Fidelity FnCas9.

In this study, we present the development of the Mutation tagging by CRISPR-based Ultra-precise Targeted Elimination in Sequencing (MUTE-Seq) method. We engineered a highly precise advanced-fidelity FnCas9 variant, named FnCas9-AF2, to effectively discriminate single-base mismatches at all positions of the single guide RNA (sgRNA) target sequences. FnCas9-AF2 exhibited significantly lower off-target effects compared to existing high-fidelity CRISPR-Cas9 variants. MUTE-Seq leverages FnCas9-AF2 for the enrichment of mutant DNA through the exclusive cleavage of perfectly matched wild-type DNA, allowing for sensitive detection of low-frequency cancer-associated mutant alleles. MUTE-Seq enabled sensitive monitoring of minimal residual disease (MRD) from the bone marrow of patients with Acute Myeloid Leukemia (AML). Furthermore, MUTE-Seq was applied in a multiplexed manner on cell-free DNA (cfDNA) from patients diagnosed with non-small cell lung cancer (NSCLC) and pancreatic cancer. This approach demonstrated a significant improvement in the sensitivity of simultaneous mutant detection and highlighted its clinical utility for early-stage cancer patients with extremely low levels of circulating tumor DNA (ctDNA). We anticipate that the FnCas9-AF2-based MUTE-Seq could offer a valuable clinical tool to facilitate improved molecular diagnosis, prognosis evaluation, and treatment planning for cancers in various stages.

PMID: 40842147 [Indexed for MEDLINE]

43. Mol Cancer. 2025 Nov 3;24(1):278. doi: 10.1186/s12943-025-02488-3.

Lung endothelial PEAR1 induces tumor cell dormancy.

In many cancer patients, distant metastases develop after years of dormancy. Understanding how disseminated tumor cells (DTCs), which are often found in proximity to the microvasculature, remain dormant and what regulates their reactivation is one of the major challenges in tumor biology. In a screen for endothelial secreted and plasma membrane proteins able to regulate tumor cell dormancy, we identified the transmembrane protein platelet and endothelial aggregation receptor 1 (PEAR1). Human and murine endothelial cells lacking PEAR1 lost the ability to promote dormancy of different tumor cells, and the extracellular part of PEAR1 was able to rescue this effect. Similarly, in mice lacking PEAR1 in endothelial cells, tumor cell dormancy in the lung was reduced and tumor metastasis was increased. We found that PEAR1 induces tumor cell dormancy by binding lysyl oxidase like 2 (LOXL2) and cathepsin D (CTSD), which both inhibit tumor cell dormancy and promote tumor growth and metastasis. Tumor cells with suppressed CTSD expression showed increased dormancy and decreased metastatic potential in vivo. Our data identify a mechanism underlying tumor cell dormancy and suggest CTSD and LOXL2 as targets for approaches to promote dormancy.

PMID: 41185039 [Indexed for MEDLINE]

44. Lancet. 2025 Nov 1;406(10515):2078-2088. doi: 10.1016/S0140-6736(25)01848-3. Epub 2025 Oct 19.

Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): a randomised, double-blind, phase 3 trial.

BACKGROUND: Squamous non-small-cell lung cancer (NSCLC) is associated with worse clinical outcomes than non-squamous NSCLC, but treatment options are scarce. We aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC.

METHODS: We conducted a randomised, double-blind, phase 3 trial at 50 sites across China (HARMONi-6). Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive intravenous ivonescimab (20 mg/kg) or tislelizumab (200 mg), plus intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve 5 mg/mL per min) once every 3 weeks for four cycles, followed by ivonescimab (20 mg/kg) or tislelizumab (200 mg) monotherapy as maintenance treatment for up to 24 months. Randomisation was stratified by disease stage (IIIB or IIIC vs IV) and PD-L1 tumour proportion score (≥1% vs<1%). The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrial.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up.

FINDINGS: From Aug 17, 2023, to Jan 21, 2025, 761 patients were screened for eligibility, among whom 532 (70%) patients were enrolled and randomly assigned to receive ivonescimab plus chemotherapy (266 [50%] patients) or tislelizumab plus chemotherapy (266 [50%] patients). As of Feb 28, 2025, median follow-up time was 10·3 months (95% CI 9·5-11·0). Median progression-free survival was 11·1 months (95% CI 9·9-not evaluable) in the ivonescimab group and 6·9 months (5·8-8·6) in the tislelizumab group (hazard ratio 0·60 [95% CI 0·46-0·78]; one-sided p<0·0001). The progression-free survival benefit with ivonescimab plus chemotherapy was consistent regardless of PD-L1 status. 170 (64%) patients in the ivonescimab group and 144 (54%) patients in the tislelizumab group had grade 3 or higher treatment-related adverse events, with grade 3 or higher immune-related adverse events occurring in 24 (9%) patients in the ivonescimab group and in 27 (10%) patients in the tislelizumab group. Grade 3 or higher treatment-related haemorrhage occurred in five (2%) patients in the ivonescimab group and in two (1%) patients in the tislelizumab group.

INTERPRETATION: In patients with untreated advanced squamous NSCLC, ivonescimab plus chemotherapy showed significantly improved progression-free survival compared with tislelizumab plus chemotherapy, regardless of PD-L1 status, as well as a manageable safety profile. This regimen could be used as a novel first-line treatment in this patient group.

FUNDING: Akeso Biopharma.

PMID: 41125109 [Indexed for MEDLINE]

45. Nat Genet. 2025 Nov;57(11):2728-2742. doi: 10.1038/s41588-025-02345-5. Epub 2025 Oct 27.

Cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma.

Most patients with localized pancreatic ductal adenocarcinoma (PDAC) experience recurrence after resection. Analysis of 744 patients with resected PDAC revealed that patients with initial isolated liver-metastatic recurrence (n = 100) had significantly worse overall survival than those with initial isolated lung-metastatic recurrence (n = 31). Using single-nucleus RNA sequencing in a representative cohort, we found that transcriptional profiles of primary cancer cells with liver-metastatic recurrence and lung-metastatic recurrence were correlated with those of normal liver and lung parenchymal cells, respectively, suggesting adoption of organ-specific metastatic programs at the primary site. These signatures were confirmed in transcriptomes of PDAC lung and liver metastases, primary lung and liver tumors, and organotropic PDAC xenograft models. These signatures were independent of large genomic events, and analysis of large-scale tumor profiling data showed no genetic alterations predictive of recurrence patterns. Additional analyses suggested that metastatic recurrence may be determined early in tumorigenesis and influenced by tumor-infiltrating immune cells. Thus, pre-existing cellular states within primary tumors appear to guide organ-specific metastatic relapse.

PMID: 41145870 [Indexed for MEDLINE]

46. Nat Cancer. 2025 Nov;6(11):1857-1879. doi: 10.1038/s43018-025-01053-7. Epub 2025 Oct 7.

A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.

Update of

    bioRxiv. 2024 Feb 14:2023.06.28.546977. doi: 10.1101/2023.06.28.546977.

Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274-PDCD1 and PVR-TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.

PMID: 41057692 [Indexed for MEDLINE]