PubMed

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

Filters applied: from 2025/10/1 - 2025/10/31.

1. Ann Oncol. 2025 Oct;36(10):1132-1141. doi: 10.1016/j.annonc.2025.06.003. Epub 2025 Jun 18.

DNA methyltransferase 3A (DNMT3A) mutations and PD-(L)1 blockade efficacy innon-small-cell lung cancer.

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BACKGROUND: Despite significant improvements in overall survival with programmed cell death protein (ligand) 1 [PD-(L)1] inhibition, most patients with metastatic non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibition (ICI). Growing evidence suggests the importance of genomic alterations in modulating anticancer immune response and predicting ICI efficacy. However, the genomic correlates of response to ICI in NSCLC are largely unknown.

DESIGN: Patients with advanced NSCLC treated with ICI and comprehensive genomic profiling from multiple independent cohorts were included. Beta-binomial modelling of sequencing read counts was used to infer mutation clonality. NSCLC samples from Cancer Genome Atlas Program (TCGA) and NSCLC cell lines from Cancer Cell Lines Encyclopedia (CCLE) were used for transcriptomic analyses.

RESULTS: Among 1539 NSCLCs, we identified deleterious DNA methyltransferase 3A (DNMT3A) mutations in 4.7% of cases. Patients with DNMT3A-mutant NSCLC had improved response rate (41.7% versus 21.5%, P < 0.001), progression-free survival [hazard ratio (HR) 0.61, P < 0.001], and overall survival (HR 0.66, P < 0.01) with PD-(L)1 blockade, compared with DNMT3A wild-type cases. DNMT3A mutations had no impact on OS among patients with advanced NSCLC who did not receive ICI (HR 0.88, P = 0.41). In examining the impact of DNMT3A clonality on immunotherapy outcomes to account for potential clonal hematopoiesis of indeterminate potential contamination, we confirmed that clonal DNMT3A mutations were associated with improved outcomes compared with DNMT3A wild-type cases. In NSCLC cell lines with pathogenic DNMT3A mutations, DNMT3A RNA and protein expression were decreased. In the TCGA, NSCLCs with high versus low DNMT3A expression exhibited lowered expression of pathways involved in innate and adaptive immune response, including interferon-γ (INFγ), major histocompatibility complex (MHC)-II antigen presentation, tumor necrosis factor-α (TNF-α), and PD-1 signaling.

CONCLUSION: Somatic DNMT3A mutations can be detected in a fraction of NSCLCs and are associated with a decreased DNMT3A expression and a favorable immunophenotype, and predict improved ICI efficacy.

PMID: 40541864 [Indexed for MEDLINE]

2. Nature. 2025 Oct;646(8083):190-197. doi: 10.1038/s41586-025-09398-w. Epub 2025 Aug 13.

Clone copy number diversity is linked to survival in lung cancer.

Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies. ALPACA estimates the SCNA evolution of simulated tumours with a higher accuracy than current state-of-the-art methods1-4. ALPACA uncovers loss-of-heterozygosity and amplification events in minor clones that may be missed using standard approaches and reveals the temporal order of somatic alterations. Analysing clone-specific copy numbers in TRACERx421 lung tumours5,6, we find evidence of increased chromosomal instability in metastasis-seeding clones and enrichment for losses affecting tumour suppressor genes and amplification affecting CCND1. Furthermore, we identify increased SCNA rates in both tumours with polyclonal metastatic dissemination and tumours with extrathoracic metastases, and an association between higher clone copy number diversity and reduced disease-free survival in patients with lung cancer.

PMID: 40804524 [Indexed for MEDLINE]

3. Cancer Cell. 2025 Oct 13;43(10):1833-1849.e10. doi: 10.1016/j.ccell.2025.06.012. Epub 2025 Jul 3.

Subclonal immune evasion in non-small cell lung cancer.

Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.

PMID: 40614739 [Indexed for MEDLINE]

4. Nat Cancer. 2025 Oct;6(10):1676-1692. doi: 10.1038/s43018-025-01018-w. Epub 2025 Jul 22.

Combination of pembrolizumab and radiotherapy induces systemic antitumor immune responses in immunologically cold non-small cell lung cancer.

The abscopal effects of radiation may sensitize immunologically cold tumors to immune checkpoint inhibition. We investigated the immunostimulatory effects of radiotherapy leveraging multiomic analyses of serial tissue and blood biospecimens (n = 293) from a phase 2 clinical trial of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in metastatic non-small cell lung cancer (NCT02492568). Participants with immunologically cold tumors (low tumor mutation burden, null programmed death ligand 1 expression or Wnt pathway mutations) had significantly longer progression-free survival in the SBRT arm. Induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after SBRT in nonirradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor (abscopal) and the blood (systemic) compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. These findings support the systemic immunomodulatory and antitumor effects of radioimmunotherapy and may open a therapeutic window of opportunity to overcome immunotherapy resistance.

PMID: 40696153 [Indexed for MEDLINE]

5. J Thorac Oncol. 2025 Oct;20(10):1369-1391. doi: 10.1016/j.jtho.2025.05.024. Epub 2025 Jun 3.

Advances in Lung Cancer Basic and Translational Research in 2025 - Overview and Perspectives Focusing on NSCLC.

Basic and translational research in lung cancer is a rapidly evolving field with a transformational impact on early detection, diagnosis, therapeutic development, and personalization of care. Recent advances have greatly increased our understanding of the molecular genomics, proteomics, pathogenesis, and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprogramming, immunobiology, the immune microenvironment, and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.

PMID: 40473107 [Indexed for MEDLINE]

6. J Thorac Oncol. 2025 Oct;20(10):1538-1547. doi: 10.1016/j.jtho.2025.05.023. Epub 2025 Jun 4.

Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.

INTRODUCTION: The PHAROS primary analysis revealed robust antitumor activity and acceptable safety with encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report results after 18 months of additional follow-up.

METHODS: In this ongoing open-label, single-arm, phase 2 study, patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. Primary end point was objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

RESULTS: At this data cutoff, median treatment duration with encorafenib plus binimetinib was 16.3 months in treatment-naive and 5.5 months in previously treated patients; minimum follow-up was approximately 32 and 22 months, respectively. In treatment-naive patients, the ORR was 75%, median DOR was 40.0 months, median PFS was 30.2 months, median OS was not estimable (95% confidence interval: 31.3-not estimable), and the 3-year OS probability was 53%. In previously treated patients, the ORR was 46%, median DOR was 16.7 months, median PFS was 9.3 months, median OS was 22.7 months, and the 3-year OS probability was 29%. Overall, the most frequent treatment-related adverse events were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). Treatment-related adverse events led to dose reductions and permanent treatment discontinuations in 25 (26%) and 16 (16%) patients, respectively.

CONCLUSIONS: With longer follow-up, encorafenib plus binimetinib showed durable and clinically meaningful antitumor activity, especially in treatment-naive patients, with a manageable safety profile in patients with BRAF V600E-mutant mNSCLC.CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT03915951.

PMID: 40480428 [Indexed for MEDLINE]

7. J Thorac Oncol. 2025 Oct;20(10):1505-1516. doi: 10.1016/j.jtho.2025.05.019. Epub 2025 Jun 3.

Treatment-Free Survival Over 6 Years of Follow-up in Patients With Metastatic NSCLC Treated With First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in CheckMate 227 Part 1.

INTRODUCTION: Treatment-free survival (TFS) characterizes periods of disease control and durable clinical benefit after treatment discontinuation in patients treated with immunotherapy. In CheckMate 227 Part 1, nivolumab plus ipilimumab reported long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic NSCLC. Here, we report updated long-term TFS results.

METHODS: This analysis included all patients randomized (tumor programmed death ligand 1 [PD-L1] expression ≥1% and<1%). TFS was estimated as the restricted-mean survival time (between Kaplan-Meier curves for time to treatment discontinuation and time to subsequent systemic therapy or death) over 6 years after randomization. TFS was further divided into periods with or without ongoing toxicity (grade 3 or greater treatment-related adverse events) and estimated over 2 and 6 years after randomization.

RESULTS: At 6 years after randomization (minimum follow-up: 73.5 months [∼6.1 years]), the estimated OS rate was 20% with nivolumab plus ipilimumab versus 11% with chemotherapy; 13% versus 2% of patients were treatment free. The 6-year mean TFS was 12.2 versus 5.0 months (difference 7.2 [95% confidence interval: 5.4-9.2]), with 17% versus 7% of the 6-year period spent in TFS. The 6-year mean TFS without grade 3 or greater treatment-related adverse events was 11.6 versus 4.8 months (difference, 6.9 [95% confidence interval: 5.1-8.9]). The proportion of mean TFS time increased from 15% of a 2-year to 17% of a 6-year period with nivolumab plus ipilimumab but decreased from 14% to 7% with chemotherapy. Similar results were observed by tumor PD-L1 expression.

CONCLUSIONS: Nivolumab plus ipilimumab improved TFS versus chemotherapy, regardless of tumor PD-L1 expression, supporting its use as an efficacious first-line treatment for metastatic NSCLC.

PMID: 40473108 [Indexed for MEDLINE]

8. Nat Genet. 2025 Oct;57(10):2482-2493. doi: 10.1038/s41588-025-02351-7. Epub 2025 Oct 10.

Spatial signatures for predicting immunotherapy outcomes using multi-omics in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) shows variable responses to immunotherapy, highlighting the need for biomarkers to guide patient selection. We applied a spatial multi-omics approach to 234 advanced NSCLC patients treated with programmed death 1-based immunotherapy across three cohorts to identify biomarkers associated with outcome. Spatial proteomics (n = 67) and spatial compartment-based transcriptomics (n = 131) enabled profiling of the tumor immune microenvironment (TIME). Using spatial proteomics, we identified a resistance cell-type signature including proliferating tumor cells, granulocytes, vessels (hazard ratio (HR) = 3.8, P = 0.004) and a response signature, including M1/M2 macrophages and CD4 T cells (HR = 0.4, P = 0.019). We then generated a cell-to-gene resistance signature using spatial transcriptomics, which was predictive of poor outcomes (HR = 5.3, 2.2, 1.7 across Yale, University of Queensland and University of Athens cohorts), while a cell-to-gene response signature predicted favorable outcomes (HR = 0.22, 0.38 and 0.56, respectively). This framework enables robust TIME modeling and identifies biomarkers to support precision immunotherapy in NSCLC.

PMID: 41073787 [Indexed for MEDLINE]

9. Ann Oncol. 2025 Oct;36(10):1142-1153. doi: 10.1016/j.annonc.2025.06.001. Epub 2025 Jun 16.

Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases.

BACKGROUND: Despite the intracranial efficacy of osimertinib, central nervous system (CNS) metastases remain a major cause of morbidity and mortality in EGFR-mutant non-small-cell lung cancer (NSCLC). The genomic drivers of CNS dissemination are poorly understood.

PATIENTS AND METHODS: We analyzed the clinicogenomic features of patients with EGFR-mutant NSCLC receiving first-line osimertinib with extracranial next generation sequencing (NGS) (n = 262) and individuals with intracranial NGS (n = 81). Paired extra- and intracranial NGS was available for 14 patients. Time-to-event analyses were conducted from time of metastatic diagnosis, except for time-to-treatment discontinuation (TTD), which began at treatment initiation.

RESULTS: Among 262 patients receiving first-line osimertinib, 53% developed CNS metastases (36% de novo, 16% acquired on treatment). The cumulative incidence of brain (BrM) and leptomeningeal metastases (LM) was 39% and 2% at 1 year, 49% and 6% at 3 years, and 54% and 12% at 5 years, respectively. CNS metastases correlated with a higher frequency of CARD11 amplifications (14% versus 3%, P = 0.031) and a lower frequency of MDM2 amplifications (1% versus 13%, P = 0.008) in extracranial NGS specimens, with otherwise similar genomic profiles. Patients who developed CNS metastases on treatment had worse overall survival (OS) [hazard ratio (HR) = 3.67, 95% confidence interval (CI) 2.41 to 5.59], followed by those with de novo (HR = 1.61, 95% CI 1.15 to 2.26), compared with those who never developed CNS metastases (P < 0.001). In multivariable Cox regression, atypical EGFR mutations were associated with shorter OS. Cell cycle pathway alterations were more frequent in BrM than LM samples (93% versus 47%, P = 0.003, q = 0.03). No other significant genomic differences were found between BrM and LM, or between paired CNS and systemic samples.

CONCLUSIONS: Patients with atypical EGFR mutations or acquired CNS metastases on osimertinib have worse outcomes. Comparative NGS profiling of intra- and extracranial tumors suggest that CNS dissemination is driven by mechanisms beyond single-gene alterations.

PMID: 40532851 [Indexed for MEDLINE]

10. Lancet Oncol. 2025 Oct;26(10):1357-1369. doi: 10.1016/S1470-2045(25)00409-7.

First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors in BRAF(V600E)-mutated metastatic non-small-cell lung cancer (FRONT-BRAF): a multicentre, retrospective cohort study.

BACKGROUND: Patients with BRAFV600E (ie, Val600Glu)-mutated non-small-cell lung cancer (NSCLC) can be treated with BRAF and mitogen-activated protein kinase (MEK) inhibitors, or with immune checkpoint inhibitors (ICIs) with or without chemotherapy. We aimed to investigate which initial systemic treatment should be prioritised in this population.

METHODS: In this retrospective cohort study conducted across 17 centres in the USA, Italy, France, and Brazil, clinicopathological data were collected from participants aged 18 years and older with stage IV, treatment-naive, metastatic BRAFV600E-mutated NSCLC and with an Eastern Cooperative Oncology Group performance status of 0-3, who started first-line treatment with ICIs with or without chemotherapy (PD-1 or PD-L1 inhibitors with or without platinum-based chemotherapy) or BRAF and MEK inhibitors (dabrafenib and trametinib or encorafenib and binimetinib) between Jan 2, 2015, and July 11, 2024. The primary endpoint was overall survival with first-line ICIs with or without chemotherapy versus with BRAF and MEK inhibitors.

FINDINGS: 284 participants were identified for this study, of whom 88 (31%) received ICIs with or without chemotherapy and 196 (69%) received BRAF and MEK inhibitors. The median age of participants was 68 years (IQR 61-74), and 148 (52%) participants were female and 136 (48%) male. Participants in the ICIs with or without chemotherapy group had a higher history of smoking (73 [83%] vs 118 [60%]; p=0·0002) and a higher PD-L1 expression (≥50% in 58 [66%] vs 76 [39%], 1-49% in 16 [18%] vs 67 [34%], and<1% in eight [9%] vs 31 [16%]; p=0·0003) than those in the BRAF and MEK inhibitor group. At a median follow-up time of 45·0 months (95% CI 39·0-55·7), ICIs with or without chemotherapy were associated with improved median overall survival compared with BRAF and MEK inhibitors (40·9 months [95% CI 33·3-not reached] vs 25·2 months [19·9-31·1]; hazard ratio [HR] 0·69 [0·49-0·98], p=0·039). In subgroup analyses, ICIs with or without chemotherapy, compared with BRAF and MEK inhibitors, were associated with longer median overall survival in participants with a history of smoking (HR 0·60 [0·40-0·90], p=0·013), with a PD-L1 tumour proportion score of ≥1% or higher (HR 0·66 [0·45-0·98], p=0·039), aged 70 years or older (HR 0·54 [0·31-0·94], p=0·029), with TP53 co-mutations (HR 0·46 [0·27-0·79], p=0·0048), and without brain metastases (HR 0·66 [0·45-0·99], p=0·045). With BRAF and MEK inhibitors, frequencies of adverse events of any grade and of grade 3 and higher were similar whether administered as first-line therapy or as second-line therapy following ICIs with or without chemotherapy.

INTERPRETATION: First-line ICIs with or without chemotherapy were associated with improved overall survival compared with BRAF and MEK inhibitors in participants with metastatic BRAFV600E-mutated NSCLC, particularly among specific subpopulations. These findings, although suggesting potential clinical relevance, remain exploratory and require confirmation from prospective studies.

PMID: 41038185 [Indexed for MEDLINE]

11. J Thorac Oncol. 2025 Oct;20(10):1441-1458. doi: 10.1016/j.jtho.2025.07.002. Epub 2025 Sep 8.

The International Association for the Study of Lung Cancer Staging Project: The Impact of Smoking Status on Lung Cancer Staging in the Ninth Edition of the TNM Classification.

INTRODUCTION: Cigarette smoking negatively affects lung cancer prognosis. Incorporating smoking history into stage-stratified survival analyses may improve prognostication.

METHODS: Using the International Association for the Study of Lung Cancer ninth edition NSCLC database, we evaluated the association between smoking status at diagnosis and overall survival (OS) using Kaplan-Meier plots and multivariate Cox proportional hazard regression models adjusted for age, region, sex, histologic type, performance status, and TNM stage. Subgroup analyses evaluated within- and between-stage survival according to smoking status. Recursive partitioning analysis evaluated the effect of smoking relative to anatomical staging factors.

RESULTS: Among 48,531 patients, 26%, 41%, and 34% currently, formerly, or never smoked, respectively; 75% had adenocarcinoma and 21%, squamous cell carcinoma. Compared with those who never smoked, those who currently (adjusted hazard ratio [aHR] = 1.39, 95% confidence interval [CI] [1.34-1.46], p < 0.0001) or formerly (aHR = 1.32, 95% CI: 1.27-1.36, p < 0.0001) smoked had worse OS. Current smoking was associated with worse OS (aHR = 1.05, 95% CI: 1.02-1.06] p = 0.005) compared with former smoking. These associations were consistent within each stage. In pair-wise comparisons, those who formerly or currently smoked had similar OS to patients in the next higher stage who never smoked. These associations remained consistent among patients from Asia, patients with adenocarcinoma, and both sexes. In recursive partitioning analysis, among patients with early stage (up to T3N1M0), smoking had greater prognostic impact than N0 versus N1 categories.

CONCLUSIONS: Smoking is an important prognostic factor and may be more impactful on prognosis than anatomical staging. Further exploration of combining smoking status with TNM classification for lung cancer is planned in the tenth edition International Association for the Study of Lung Cancer staging project.

PMID: 40920143 [Indexed for MEDLINE]

12. Mol Cancer. 2025 Oct 2;24(1):234. doi: 10.1186/s12943-025-02439-y.

P23 acts as a negative regulator of ferroptosis in NSCLC by blocking GPX4 degradation via chaperone-mediated autophagy.

Ferroptosis has been identified as a tumor-inhibiting event in a variety of cancers; however, its molecular basis in non-small cell lung cancer (NSCLC) has not been completely elucidated. Notably, glutathione peroxidase 4 (GPX4) plays a crucial role in ferroptosis. Our previous research revealed that prostaglandin E synthase 3 (p23), a potential transcription factor, plays a crucial role in promoting cancer progression and metastasis through succinylation. Our study revealed a previously unknown antiferroptotic function of p23. Mechanistically, p23 stabilizes GPX4 by competitively binding heat shock cognate 71 kDa protein (HSC70) to suppress chaperone-mediated autophagy (CMA) activity, which subsequently inhibits ferroptosis and accelerates tumor growth. Notably, impairing p23 succinylation disrupts its interaction with HSC70, restoring CMA-mediated GPX4 degradation. Collectively, our findings suggest that targeting p23-regulated CMA pathways represents a potentially viable strategy to modulate ferroptosis in NSCLC.

PMID: 41039570 [Indexed for MEDLINE]

13. Adv Mater. 2025 Oct;37(42): e04987. doi: 10.1002/adma.202504987. Epub 2025 Aug 2.

A Noninvasive and Highly Effective Inhaled Nanovaccine Based on Natural Polysaccharide for Lung Cancer Treatment.

Lung cancer is the most widespread malignancy globally and the leading cause of cancer-related deaths, highlighting the need for innovative treatments. Herein, a novel inhaled vaccine carrier is presented by modifying dextran (Dex) with N,N-dimethylethylenediamine (DMEN) and 4-(bromomethyl)phenylboronic acid (PBA) (Dex-DMEN-PBA, DDP). The optimized DDP demonstrates a potent adjuvant effect in promoting dendritic cell (DC) maturation by multiple signaling pathways. Moreover, the nanovaccine (DDP/Lewis lung carcinoma (LLC)) forms through electrostatic interactions between DDP and protein antigens derived from LLC cells. Upon inhalation, it induces DC maturation, T cell activation, and germinal center B cell activation in the thoracic lymph node. In the mouse model, the inhaled DDP/LLC nanovaccine displays impressive prophylactic effects against lung cancer, with 50% of mice alive after six months and 33% surviving a subsequent challenge, indicating strong long-term immune memory. Remarkably, it surpasses subcutaneous vaccination, particularly in activating germinal center B cells and follicular helper T (Tfh) cells, and upregulating tissue-resident memory T (TRM) cells in the lung. This self-adjuvant nanovaccine effectively prevents tumor growth and induces robust immune memory, offering valuable insight for treating lung cancer and related diseases.

PMID: 40751561 [Indexed for MEDLINE]

14. 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]

15. Signal Transduct Target Ther. 2025 Oct 16;10(1):347. doi: 10.1038/s41392-025-02445-y.

Circulating tumor DNA refines consolidation immunotherapy for limited-stage small cell lung cancer patients.

Despite the lack of predictive biomarkers and a prognostic stratification strategy, immune checkpoint inhibitor (ICI) has shown promise in improving outcomes for patients with limited-stage small cell lung cancer (LS-SCLC). We evaluated the potential of circulating tumor DNA (ctDNA) to dynamically predict outcomes in patients with LS-SCLC receiving concurrent chemoradiotherapy (CCRT) with or without consolidation ICI. We analyzed 490 serial samples collected from 144 LS-SCLC patients at baseline (t0), post-induction chemotherapy and pre-thoracic radiotherapy (t1), post-radiotherapy (t2), and progressive disease (t3). For 44 patients receiving consolidation ICI with serplulimab, an investigational PD-1 inhibitor, ctDNA dynamics during consolidation ICI were also assessed at multiple time points. Patients with undetectable ctDNA after CCRT had good outcomes with or without consolidation ICI, whereas ctDNA-positive patients at t2, indicating poor response to CCRT, derived survival benefit from consolidation ICI. Notably, ctDNA status at t1 appeared more predictive than at t2. A three-level risk stratification strategy integrating t1 ctDNA status with radiological tumor shrinkage identified a high-risk subgroup of patients who achieved significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.08-0.75; p = 0.014) and overall survival (OS) (HR, 0.06; 95% CI, 0.00-0.42; p = 0.001) from consolidation ICI, prioritizing CCRT plus consolidation ICI. Furthermore, maintaining ctDNA negativity during consolidation ICI was associated with favorable outcomes. These data provide valuable insights into the individualized management of LS-SCLC in the era of immunotherapy.

PMID: 41093826 [Indexed for MEDLINE]

16. Cancer Res. 2025 Oct 15;85(20):3821-3822. doi: 10.1158/0008-5472.CAN-25-4003.

Precision Epigenetic Reprogramming: CoREST Inhibition Sensitizes STK11-Mutant Tumors to Immune Checkpoint Blockade Therapy.

Loss-of-function mutations in STK11 (also known as LKB1) define a molecular subtype of non-small cell lung cancer that is resistant to immune checkpoint blockade therapy, partially owing to impaired T-cell infiltration and suppressed antigen presentation. Emerging evidence implicates epigenetic deregulation as a key driver of immune evasion in STK11-mutant tumors. In this issue of Cancer Research, Ahronian and colleagues identified the CoREST complex, via histone deacetylase 1, as a vulnerability that can be targeted pharmacologically to restore immune sensitivity in STK11-mutant tumors. The authors developed TNG260, a selective small-molecule CoREST inhibitor with favorable pharmacologic properties and reduced toxicity relative to pan-histone deacetylase inhibitors. In preclinical models of STK11-deficient non-small cell lung cancer, TNG260 reprograms the tumor epigenome to upregulate immune genes and synergizes with anti-PD-1 therapy to induce durable tumor regressions. Early clinical data from an ongoing trial (NCT05887492) show increased histone acetylation and CD8+ T-cell infiltration in patient tumors treated with TNG260 and pembrolizumab. This commentary places these findings in the broader context of epigenetic modulation of antitumor immune response. We also outline key questions for future investigation, including durability of immune response, tumor-type specificity, and biomarker strategies for patient selection and response monitoring. See related article by Ahronian et al., p. 3966.

PMID: 41088878 [Indexed for MEDLINE]

17. Mol Cancer. 2025 Oct 28;24(1):272. doi: 10.1186/s12943-025-02493-6.

IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Despite an initial favorable response of EGFR-mutant non-small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear.

METHODS: To identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR-mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model.

RESULTS: Transcriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model.

CONCLUSIONS: Our findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR-mutant NSCLC.

PMID: 41152910 [Indexed for MEDLINE]

18. J Clin Oncol. 2025 Oct;43(28):3081-3089. doi: 10.1200/JCO-25-00610. Epub 2025 Jul 21.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity-Dominant Lung Adenocarcinoma.

Comment in

    doi: 10.1200/JCO-25-01578.

PURPOSE: Systematic mediastinal lymph node dissection (LND) or sampling is currently recommended for patients with early-stage non-small cell lung cancer. We aimed to investigate whether no mediastinal LND was noninferior to systematic LND in patients with ground glass opacity (GGO)-dominant invasive lung adenocarcinoma.

METHODS: We conducted a multicenter, open-label, phase III, noninferiority randomized controlled trial comparing systematic mediastinal LND versus no mediastinal LND in patients with GGO-dominant invasive lung adenocarcinoma, who were predicted to have no lymph node metastasis on the basis of criteria established in our previous trial. The primary end point was 3-year disease-free survival. An interim analysis was planned upon enrollment of 300 patients, with predefined termination criteria if no mediastinal lymph node metastasis is detected and life-threatening complications occur in the systematic LND arm. This trial is registered on ClinicalTrials.gov (ECTOP-1009, identifier: NCT04527419).

RESULTS: Interim analysis of 302 patients revealed no lymph node metastasis in either study arm. The no LND arm had significantly reduced surgery duration (mean, 74 minutes v 109 minutes; P < .001), blood loss (mean, 44 mL v 82 mL; P = .033), and postoperative hospital stay (mean, 3.9 days v 4.5 days; P = .002). Complications observed in the systematic LND arm included chylothorax in one patient (0.7%) and intraoperative massive bleeding because of superior vena cava injury in one patient (0.7%). No lymphadenectomy-related complications occurred in the no LND arm.

CONCLUSION: On the basis of interim findings and the principle of nonmaleficence, the trial should be terminated. Systematic mediastinal LND should no longer be recommended for patients with GGO-dominant lung adenocarcinoma.

PMID: 40690727 [Indexed for MEDLINE]

19. Lancet Oncol. 2025 Oct;26(10):1300-1311. doi: 10.1016/S1470-2045(25)00480-2. Epub 2025 Sep 8.

Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study.

BACKGROUND: Tarlatamab is a delta-like ligand 3 (DLL3)-directed bispecific T-cell engager immunotherapy that has improved survival in patients with previously treated small-cell lung cancer (SCLC). We evaluated the safety and activity of tarlatamab in combination with atezolizumab or durvalumab as first-line maintenance therapy in patients with extensive-stage (ES)-SCLC.

METHODS: In this multicentre, non-randomised, phase 1b study, patients aged 18 years and older, with Eastern Cooperative Oncology Group performance status of 0-1 and without disease progression after four to six cycles of platinum-etoposide chemotherapy plus a programmed cell death ligand 1 (PD-L1) inhibitor (if available), received tarlatamab 10 mg intravenously once every 2 weeks, after an initial tarlatamab 1 mg dose, with atezolizumab intravenously (1680 mg once every 4 weeks) or durvalumab intravenously (1500 mg once every 4 weeks) as maintenance until disease progression. Patients were enrolled from 30 centres in 13 countries. The primary objective was to evaluate safety and to determine the recommended phase 2 dose or maximum tolerated dose of tarlatamab in combination with a PD-L1 inhibitor through assessment of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, and clinical laboratory tests. All patients who received at least one dose of tarlatamab were included in the analyses. Because overall survival data were immature at the primary analysis, in this Article, we report a non-specified interim analysis to provide an updated examination of overall survival and longer-term safety. This study is registered with ClinicalTrials.gov, NCT05361395; the EU Clinical Trials registry, 2021-005462-17; and EudraCT, 2024-511021-58.

FINDINGS: Between Aug 31, 2022, and Jan 30, 2024, 88 patients received tarlatamab with atezolizumab or durvalumab after standard-of-care first-line chemo-immunotherapy. The median time from start of standard-of-care first-line chemo-immunotherapy to start of tarlatamab maintenance was 3·6 months (IQR 3·2-4·3). The median follow-up from the start of maintenance was 18·4 months (15·2-23·0) and the median exposure to tarlatamab was 35 weeks (8-75). The most common grade 3-4 adverse events were hyponatraemia (nine [10%] of 88 patients), anaemia (seven [8%] of 88 patients), and neutropenia (six [7%] of 88 patients). Serious adverse events occurred in 50 (57%) of 88 patients. The most common serious adverse events were cytokine release syndrome (21 [24%] of 88 patients), pyrexia (six [7%] of 88 patients), immune effector cell-associated neurotoxicity syndrome (four [5%] of 88 patients), and pneumonia (four [5%] of 88 patients). There were no deaths due to treatment-related adverse events. Median overall survival was 25·3 months (95% CI 20·3-not estimable).

INTERPRETATION: Tarlatamab plus a PD-L1 inhibitor as maintenance after first-line chemo-immunotherapy showed a manageable safety profile with promising anticancer activity, supporting the ongoing phase 3 trial (NCT06211036).

PMID: 40934933 [Indexed for MEDLINE]

20. J Clin Oncol. 2025 Oct 20;43(30):3249-3253. doi: 10.1200/JCO-25-00040. Epub 2025 Jul 9.

Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study.

Divarasib (GDC-6036), an oral, highly potent and selective next-generation KRAS G12C inhibitor, has demonstrated a manageable safety profile and promising antitumor activity in patients with advanced KRAS G12C-positive non-small cell lung cancer (NSCLC). Here, we report long-term (≥1 year) follow-up of single-agent divarasib from the ongoing, open-label, and multicenter phase I study (ClinicalTrials.gov identifier: NCT04449874). The primary objective was safety, and the other objectives included preliminary antitumor activity. Overall, 65 patients with advanced KRAS G12C-positive NSCLC received single-agent oral divarasib 50-400 mg once daily and 31 patients (48%) were treated beyond 1 year. Divarasib continued to be well tolerated, and the safety profile beyond 1 year was consistent with the overall safety profile. In patients with measurable disease at baseline across all dose levels (n = 63), the confirmed objective response rate was 55.6% (95% CI, 42.5 to 68.1), and the median duration of response was 18.0 months (95% CI, 11.1 to 24.9). The median progression-free survival was 13.8 months (95% CI, 9.8 to 25.4) in the overall population (N = 65) and 15.3 months (95% CI, 12.3 to 26.1) among patients assigned to the 400-mg dose level (n = 44). With extended follow-up, divarasib demonstrated long-term safety and antitumor activity in patients with advanced KRAS G12C-positive NSCLC.

PMID: 40632992 [Indexed for MEDLINE]

21. J Clin Oncol. 2025 Oct 10;43(29):3198-3208. doi: 10.1200/JCO-25-00788. Epub 2025 Sep 9.

Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B).

PURPOSE: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins).

METHODS: Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)-assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR).

RESULTS: Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance (P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%).

CONCLUSION: Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.

PMID: 40923280 [Indexed for MEDLINE]

22. J Thorac Oncol. 2025 Oct;20(10):1517-1530. doi: 10.1016/j.jtho.2025.07.117. Epub 2025 Sep 9.

Enhanced Versus Standard Dermatologic Management With Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC: The COCOON Global Randomized Controlled Trial.

INTRODUCTION: Amivantamab plus lazertinib significantly improved progression-free and overall survival versus osimertinib in patients with previously untreated, EGFR-mutant advanced NSCLC. EGFR-targeted therapies are associated with dermatologic adverse events (AEs), which can affect quality of life (QoL). COCOON was conducted to assess prophylactic management and improve treatment experience.

METHODS: In the phase 2 COCOON study (NCT06120140), participants with previously untreated, EGFR-mutant, locally advanced or metastatic NSCLC received intravenous amivantamab plus oral lazertinib and were randomized 1:1 to enhanced dermatologic management (COCOON DM) or standard of care (SoC DM) per local guidelines. COCOON DM included oral doxycycline or minocycline (100 mg twice daily; weeks 1-12), clindamycin 1% (on scalp daily; weeks 13-52), chlorhexidine 4% (on fingernails and toenails daily), and ceramide-based moisturizer (on body and face at least daily). Primary end point was incidence of grade 2 or higher dermatologic AEs of interest (DAEIs) by week 12.RESULTS: In total, 201 participants were randomized (99 to COCOON DM and 102 to SoC DM). At a median follow-up of 7.1 months, COCOON DM demonstrated significant reduction in the primary end point versus SoC DM (42% versus 75%; OR, 0.24; 95% confidence interval, 0.13-0.45; p < 0.0001). By week 12, the largest benefit with COCOON DM was observed in DAEIs involving the face and body (excludes paronychia; 26% versus 60%; p < 0.0001) and DAEIs involving the scalp (10%

versus 26%; p = 0.0049). This benefit was maintained at 6 months, with significant reductions of DAEIs involving face, body, and scalp (excluding paronychia). Patient-reported outcomes favored COCOON DM, indicating reduced impact of dermatologic symptoms on QoL.

CONCLUSION: An uncomplicated, widely available, prophylactic regimen (COCOON DM) reduced the incidence of DAEIs with amivantamab-lazertinib and the impact of symptoms on QoL.

PMID: 40923969 [Indexed for MEDLINE]

23. 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]

24. Cancer Commun (Lond). 2025 Oct;45(10):1285-1308. doi: 10.1002/cac2.70052. Epub 2025 Jul 24.

m(6)A-modified EHD1 controls PD-L1 endosomal trafficking to modulate immune evasion and immunotherapy responses in lung adenocarcinoma.

BACKGROUND: Eps15 homology domain (EHD) proteins, including EHD1 to EHD4, play vital roles in tumor progression. In this study, we aimed to investigate which specific EHD proteins, if any, are implicated in tumor immune evasion and immunotherapy response.

METHODS: The immunotherapy responses of lung adenocarcinoma (LUAD) patients were predicted using tumor immune dysfunction and exclusion (TIDE) analysis. The T cell killing assay was performed by co-culturing activated T cells with LUAD cells. The function of EHD1 as a regulator of programmed death-ligand 1 (PD-L1) endocytic recycling was determined by receptor internalization assays. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate N6-methyladenosine (m6A) modification of EHD1 mRNA. The protein-protein interaction was revealed by the molecular docking analysis and validated by immunofluorescence (IF) and immunoprecipitation (IP) assays. RNA immunoprecipitation (RIP) was used to examine the interaction between YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) and EHD1 mRNA. The regulatory mechanism of YTHDF1 on EHD1 was investigated through the application of m6A-binding site mutation analysis. The murine LUAD cells were employed to establish subcutaneous xenograft models within immunocompetent C57BL/6 mice to assess the immunomodulatory impact of EHD1 in vivo.

RESULTS: TIDE algorithms and survival analysis identified that EHD1 promoted LUAD immune escape. EHD1 knockdown enhanced T cell cytotoxicity in killing LUAD cells across all effector-to-target (E/T) ratios. EHD1 overexpression exerted the opposite effect. The molecular docking analysis revealed an interaction between EHD1 and the PD-L1 protein, verified by IF and IP. Furthermore, EHD1 knockdown inhibited PD-L1 recycling, thereby promoting its lysosomal degradation. Disruption of the EHD1/PD-L1 interaction impaired the regulatory function of EHD1 in tumor immune evasion. In an immune-competent mouse model, we found that EHD1 silencing impeded tumor immune evasion and enhanced the efficacy of anti‑PD‑1 therapy. MeRIP-qPCR confirmed obvious m6A modification of EHD1. Further, the EHD1 mRNA was found to bind to the YTHDF1 protein, an m6A reader. YTHDF1 overexpression up-regulated EHD1 expression by enhancing its mRNA stability in an m6A-dependent manner.

CONCLUSION: Our study illuminates the role of m6A-modified EHD1 in tumor immune evasion and immunotherapy responses, thereby offering a novel avenue to potentially enhance immunotherapeutic sensitivity and improve the prognosis for patients with LUAD.

PMID: 40703029 [Indexed for MEDLINE]

25. J Thorac Oncol. 2025 Oct;20(10):1459-1474. doi: 10.1016/j.jtho.2025.06.007. Epub 2025 Jun 13.

Targeting WEE1 to Overcome ARID1A Mutation-Driven Osimertinib Resistance in EGFR-Mutant Lung Cancer.

INTRODUCTION: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for EGFR-mutant NSCLC. Nevertheless, despite its efficacy, resistance remains a major clinical challenge with unknown underlying mechanisms. This study aimed to investigate the mechanisms driving osimertinib resistance and identify therapeutic strategies.

METHODS: Using a mouse model of leptomeningeal carcinomatosis, we induced osimertinib resistance and performed next-generation sequencing to characterize resistance-associated mutations. We also analyzed clinical samples to correlate ARID1A status with progression-free survival and overall survival in patients receiving osimertinib.

RESULTS: Mutations in the AT-rich interacting domain-containing protein 1A (ARID1A) gene were the most prevalent in resistant cells. Functional assays revealed that ARID1A knockout in parental cells and wild-type ARID1A gene expression in resistant cells were critical in conferring osimertinib resistance. A Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 knockout screen identified WEE1 kinase as a potent enhancer of apoptosis in ARID1A-mutant osimertinib-resistant cells. Mechanistically, ARID1A-mutant cells exhibited reduced expression of genes involved in cell cycle regulation and DNA repair, rendering them particularly sensitive to WEE1 inhibition. In the leptomeningeal carcinomatosis mouse model, the combined inhibition of EGFR and WEE1 significantly suppressed tumor growth. Clinically, patients with ARID1A mutations treated with osimertinib had significantly shorter median progression-free survival (6.25 versus 18.0 months, p = 0.0036) and overall survival (17.0 versus 34.0 months, p = 0.024) than did those with wild-type ARID1A.

CONCLUSIONS: These findings suggest that ARID1A mutations are critical biomarkers for osimertinib resistance and highlight WEE1 inhibition as a promising therapeutic approach for ARID1A-mutant osimertinib-resistant NSCLC.

PMID: 40518016 [Indexed for MEDLINE]

26. Signal Transduct Target Ther. 2025 Oct 9;10(1):335. doi: 10.1038/s41392-025-02435-0.

CD8(+) TILs in necrotic tumors after neoadjuvant immunochemotherapy predict outcomes in non-small-cell lung cancer patients.

Neoadjuvant immunochemotherapy has shown promising results, with major pathologic response (MPR, ≤10% residual viable tumors [RVT]) as the primary outcome. However, %RVT showed limited predictive power in stratifying outcomes within the MPR and non-MPR groups. To identify a better prognostic marker, this study analyzed 200 non-small-cell lung cancer (NSCLC) samples after neoadjuvant PD-1 blockade combined with chemotherapy across three medical centers. Among these patients, 99 had necrotic regions in their residual lesions. We found that tumor-infiltrating lymphocytes in necrotic areas (nTILs) lose their cellular structure, but retained T-cell-specific antigens, making them detectable by immunohistochemistry. Regardless of PD-L1 status or lymph node metastasis, patients with high CD8+ nTIL density had significantly improved event-free survival (EFS) (hazard ratio [HR]: 0.08; 95% CI: [0.01-0.62]; p = 0.0019). Furthermore, CD8+ nTIL density improved prognostic predictions for patients within the MPR (p = 0.017) and non-MPR groups (p = 0.076). Radiological responses did not correlate with MPR, CD8+ nTIL density or EFS. 41.5% MPR cases were misclassified by radiological assessments. When compared with radiographic response and pathological response, CD8+ nTIL density outperformed these traditional parameters in approximating EFS. These findings demonstrate that the CD8+ nTIL density is a robust predictor of EFS in NSCLC patients treated with neoadjuvant immunochemotherapy and has great potential in guiding treatment decisions.

PMID: 41062493 [Indexed for MEDLINE]

27. J Thorac Oncol. 2025 Oct;20(10):1475-1488. doi: 10.1016/j.jtho.2025.05.021. Epub 2025 Jun 3.

Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Patients With Advanced Lung Squamous Cell Carcinoma Receiving Immunochemotherapy or Chemotherapy Alone.

INTRODUCTION: Although circulating tumor DNA (ctDNA) dynamics have been widely explored for therapeutic response assessment, standardized methodologies remain elusive. Here, we developed MinerVa-Delta, a novel approach to quantify ctDNA dynamics by calculating weighted mutation changes in samples with multiple tracked variants.

METHODS: MinerVa-Delta was developed and analytically validated using serially diluted reference samples. The optimal cutoff was determined in a discovery cohort of 227 patients with advanced lung squamous cell carcinoma (LUSC) receiving programmed cell death protein 1 blockade plus chemotherapy or chemotherapy alone and further validated in an independent cohort of 97 patients with LUSC treated with chemotherapy alone. Variants were de novo called in pretreatment samples using a 769-gene next-generation sequencing panel, serving as a basis for personalized variant tracking in posttreatment plasma after two cycles of treatment. We applied MinerVa-Delta to evaluate prognosis and therapeutic response in advanced LUSC.

RESULTS: Patients classified as molecular responders (MinerVa-Delta<30%) exhibited significantly improved outcomes compared with nonresponders (MinerVa-Delta ≥30%), with superior progression-free survival (hazard ratio = 0.19, p < 0.001) and overall survival (hazard ratio = 0.24, p < 0.001). MinerVa-Delta displayed consistent prediction performance in the validation cohort. Furthermore, MinerVa-Delta accurately identified radiologic stable disease patients, a clinically heterogeneous population, who could benefit from initial treatment.

CONCLUSIONS: Our findings suggest MinerVa-Delta is feasible for evaluating treatment response in patients with advanced LUSC. Integrating ctDNA profiling with conventional imaging could enhance response assessment, particularly in radiologic stable disease patients, enabling more precise therapeutic decision-making.

PMID: 40473106 [Indexed for MEDLINE]

28. ACS Nano. 2025 Oct 7;19(39):34708-34723. doi: 10.1021/acsnano.5c09056. Epub 2025 Sep 25.

Exploring the Potentials of Silver Nanoparticles in Overcoming Cisplatin Resistance in Lung Adenocarcinoma: Insights from Proteomic and Xenograft Mice Studies.

Silver nanoparticles (AgNPs) have shown great potential as therapeutic agents due to their ability to cause apoptotic cell death in cancer cells. However, little knowledge is available regarding the underlying action mechanisms of AgNPs toward multidrug-resistant cancer cells. Herein, we employed quantitative proteomics to investigate the cytotoxic mechanisms of AgNPs and their potential anticancer properties on both cisplatin-sensitive (A549 cells) and -resistant (A549/DDP cells) human lung adenocarcinoma using quantitative proteomics and mice xenograft model approaches. We first performed cytotoxicity tests and found that AgNPs exerted similar cytotoxic effects on A549 and A549/DDP cells. At the proteome level, A549 and A549/DDP cells responded to AgNPs distinctively and similarly by causing cell apoptosis via upregulating RNA metabolism, suppressing the VEGF signaling pathway, repressing p53-mediated pathways, promoting cell cycle arrest, etc. Additionally, we found that AgNPs induced ROS generation and disrupted mitochondrial function and respiration in the A549 and A549/DDP cells. Lastly, animal studies using established mice xenograft models administered with AgNPs showed that AgNPs exhibit similar antitumoral effects on both A549 and A549/DDP-bearing mice. Overall, our investigations showed that AgNPs could effectively induce cell death in lung adenocarcinoma regardless of their sensitivities to cisplatin, suggesting that AgNPs could be potentially used in biomedical aspects as anticancer agents in alleviating the problem of acquired drug resistance in chemotherapy.

PMID: 40999704 [Indexed for MEDLINE]

29. N Engl J Med. 2025 Nov 6;393(18):1819-1832. doi: 10.1056/NEJMoa2511065. Epub 2025 Oct 17.

Sevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: HER2 gene mutations occur in 2 to 4% of patients with non-small-cell lung cancer (NSCLC). Sevabertinib is an oral, reversible tyrosine kinase inhibitor that has shown anti-HER2 activity in preclinical models.

METHODS: We conducted an open-label, multicenter, multicohort, phase 1-2 study to evaluate sevabertinib at a twice-daily dose of 20 mg in patients with locally advanced or metastatic HER2-mutant NSCLC. Three cohorts were defined according to previous therapy: cohort D comprised previously treated patients who had not received HER2-targeted therapy; cohort E, patients who had previously received HER2-directed antibody-drug conjugates; and cohort F, patients who had not previously received treatment. The primary end point was an objective response, as assessed by blinded independent central review. Secondary end points were duration of response and progression-free survival.

RESULTS: A total of 209 patients received sevabertinib (as of June 27, 2025, the data-cutoff date); the median duration of follow-up was 13.8 months in cohort D, 11.7 months in cohort E, and 9.9 months in cohort F. Among 81 patients in cohort D, an objective response was observed in 64% (95% confidence interval [CI], 53 to 75); the median duration of response was 9.2 months (95% CI, 6.3 to 13.5), and the median progression-free survival was 8.3 months (95% CI, 6.9 to 12.3). Among 55 patients in cohort E, an objective response was observed in 38% (95% CI, 25 to 52); the median duration of response was 8.5 months, and the median progression-free survival was 5.5 months. Among 73 patients in cohort F, an objective response was observed in 71% (95% CI, 59 to 81), and the median duration of response was 11.0 months; data on progression-free survival were immature. Grade 3 or higher drug-related adverse events occurred in 31% of the patients. The most common adverse event was diarrhea (in 84 to 91%), with diarrhea of grade 3 or higher occurring in 5 to 23%. Treatment was discontinued by 3% of the patients owing to drug-related adverse events.

CONCLUSIONS: Sevabertinib showed antitumor activity in patients with locally advanced or metastatic HER2-mutant NSCLC. Diarrhea was the most common adverse

event. (Funded by Bayer; SOHO-01 ClinicalTrials.gov number, NCT05099172.).

PMID: 41104928 [Indexed for MEDLINE]

30. Nature. 2025 Oct;646(8087):1232-1242. doi: 10.1038/s41586-025-09492-z. Epub 2025 Sep 10.

Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis.

Update of

    bioRxiv. 2023 Jan 20:2023.01.19.524430. doi: 10.1101/2023.01.19.524430.

Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms1 and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses2,3. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression4-12. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron-cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

PMID: 40931074 [Indexed for MEDLINE]

31. Cell. 2025 Oct 2;188(20):5701-5716.e19. doi: 10.1016/j.cell.2025.06.027. Epub 2025 Jul 15.

Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL.

Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+ macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.

PMID: 40669460 [Indexed for MEDLINE]

32. Nature. 2025 Oct;646(8085):734-745. doi: 10.1038/s41586-025-09433-w. Epub 2025 Aug 20.

Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors.

Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity1. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10-13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A-E2F and cyclin B-MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B-CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.

PMID: 40836083 [Indexed for MEDLINE]

33. 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]

34. J Thorac Oncol. 2025 Oct;20(10):1489-1504. doi: 10.1016/j.jtho.2025.05.020. Epub 2025 Jun 3.

LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-Programmed Cell Death Protein 1 or Anti-Programmed Cell Death Ligand 1 Plus Platinum Chemotherapy.

BACKGROUND: LEAP-008 (NCT03976375) was an open-label, randomized, phase 3 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic NSCLC that progressed on anti‒programmed cell death protein 1 or anti‒programmed cell death ligand 1 therapy and platinum-containing chemotherapy.

METHODS: Participants were randomized 4:4:1 to once-daily lenvatinib 20 mg plus pembrolizumab 200 mg every 3 weeks (maximum 35 cycles), docetaxel 75 mg/m2 every 3 weeks, or once-daily lenvatinib 24 mg. Primary end points were overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by central review. The superiority of lenvatinib plus pembrolizumab versus docetaxel was assessed at interim analysis 2 for PFS and final analysis for OS.

RESULTS: Participants (N = 422) were randomized to lenvatinib plus pembrolizumab (n = 185), docetaxel (n = 189), or lenvatinib monotherapy (n = 48). The median (95% confidence interval [CI]) PFS was 5.6 (4.2‒6.5) months with lenvatinib plus pembrolizumab and 4.2 (3.2‒5.2) months with docetaxel (hazard ratio, 0.89 [95% CI: 0.70‒1.12]; p = 0.164). The median (95% CI) OS was 11.3 (9.4‒13.2) versus 12.0 (9.6‒13.7) months (hazard ratio, 0.98 [95% CI: 0.78‒1.23]; p = 0.434). Rates of treatment-related adverse events were 91.7%, 91.0%, and 89.4% with lenvatinib plus pembrolizumab, docetaxel, and lenvatinib, respectively; the rates of grade 3 to 5 treatment-related adverse events were 59.7%, 48.6%, and 57.4%. Health-related quality of life scores were similar between treatment arms.

CONCLUSION: Lenvatinib plus pembrolizumab did not improve efficacy versus docetaxel in participants with stage IV NSCLC that progressed on anti‒programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy and platinum-containing chemotherapy. There were no unexpected safety signals. More effective therapies are needed for this patient population.

PMID: 40473109 [Indexed for MEDLINE]

35. N Engl J Med. 2025 Oct 30;393(17):1681-1693. doi: 10.1056/NEJMoa2503001. Epub 2025 Sep 7.

Overall Survival with Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Previous results from this phase 3 trial showed that progression-free survival among participants with previously untreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC) was significantly improved with amivantamab-lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported.

METHODS: We randomly assigned, in a 2:2:1 ratio, participants with previously untreated EGFR-mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab-lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety.

RESULTS: A total of 429 participants each were assigned to receive amivantamab-lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P = 0.005); 3-year overall survival was 60% and 51%, respectively. At the clinical cutoff date, 38% of participants in the amivantamab-lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab-lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up.

CONCLUSIONS: Amivantamab-lazertinib led to significantly longer overall survival among participants with previously untreated EGFR-mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of grade 3 or higher. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

PMID: 40923797 [Indexed for MEDLINE]

36. Nature. 2025 Oct;646(8087):1214-1222. doi: 10.1038/s41586-025-09493-y. Epub 2025 Sep 10.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours.

Update of

    bioRxiv. 2024 Jun 28:2024.06.24.600383. doi: 10.1101/2024.06.24.600383.

Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME)1 and tumour-enhanced myelopoiesis in the bone marrow fuels these populations2. Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.

PMID: 40931076 [Indexed for MEDLINE]