PubMed：

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

Filters applied: from 2025/12/1 - 2025/12/31.

1. 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]

2. Cancer Lett. 2025 Dec 28;635:218071. doi: 10.1016/j.canlet.2025.218071. Epub 2025 Sep 30.

Loss of ADAR1 in lung cancer activates anti-tumour immunity and suppresses tumour cell growth via the RIG-I/MDA5-MAVS pathway.

Aberrant accumulation of dsDNA in tumour cells activates the cGAS-STING pathway, playing a crucial role in anti-tumour immunity. However, the role of the dsRNA sensor RIG-I-like receptor-mitochondrial antiviral signalling protein (RLR-MAVS) in anti-tumour immunity remains unclear. ADAR1 edits endogenous dsRNA by catalysing the deamination of adenosine to inosine, preventing activation of the RLR-MAVS pathway, which is vital for immune homeostasis and tissue development. In this study, we investigated the roles of ADAR1 and RLR-MAVS in anti-tumour immunity of lung cancer. Our findings revealed that knockout Adar1 induces dsRNA accumulation, activating the TBK1-IRF3 pathway and stimulating interferon stimulating genes (ISGs) expression, which in turn activates anti-tumour immunity and suppresses lung cancer growth. We demonstrated that the RIG-I/MDA5-MAVS pathway is responsible for this anti-tumour immune activation and tumour suppression, which is contrast to the effects mediated by Zbp1, another downstream molecule regulated by Adar1, which is known to drive lethal type I interferon activation and immunopathology inflammatory responses. Moreover, we found that Adar1-deficient lung cancer cells suppress abscopal homogeneous and non-homogeneous tumour growth when used as a tumour cell vaccine. Additionally, Adar1 deficiency in lung cancer cells significantly enhances the efficacy of immunotherapy when employed as adjuvant. In summary, our study elucidates the mechanism by which Adar1 deficiency activates anti-tumour immunity and inhibits tumour cell growth. These findings highlight Adar1 and the downstream RIG-I/MDA5-MAVS pathway as promising targets for immunotherapy development.

PMID: 41038563 [Indexed for MEDLINE]

3. J Clin Invest. 2025 Oct 14;135(23):e193790. doi: 10.1172/JCI193790. eCollection 2025 Dec 1.

A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non-small cell lung cancer.

The effectiveness of RAS/MAPK inhibitors in treating metastatic KRAS-mutant non-small cell lung cancer (NSCLC) is often hindered by the development of resistance driven by disrupted negative feedback mechanisms led by phosphatases like PP2A. PP2A is frequently suppressed in lung cancer to maintain elevated RAS/MAPK activity. Despite its established role in regulating oncogenic signaling, targeting PP2A with RAS/MAPK to prevent resistance has not been previously demonstrated. In this study, we aimed to establish a treatment paradigm by combining a PP2A molecular glue with a RAS/MAPK inhibitor to restore PP2A activity and counteract resistance. We demonstrated that KRASG12C and MEK1/2 inhibitors disrupted PP2A carboxymethylation and destabilized critical heterotrimeric complexes. Furthermore, genetic disruption of PP2A carboxymethylation enhanced intrinsic resistance to MEK1/2 inhibition both in vitro and in vivo. We developed RPT04402, a PP2A molecular glue that selectively stabilizes PP2A-B56α heterotrimers. In commercial cell lines and in a patient-derived model, combining RPT04402 with a RAS/MAPK inhibitor slowed proliferation and enhanced apoptosis. In mouse xenografts, this combination induced tumor regressions, extended median survival, and delayed the onset of treatment resistance. These findings highlight that promoting PP2A stabilization and RAS/MAPK inhibition presents a promising therapeutic strategy to improve treatment outcomes and overcome resistance in metastatic KRAS-mutant NSCLC.

PMID: 41086023 [Indexed for MEDLINE]

4. Nat Commun. 2025 Dec 18;16(1):11280. doi: 10.1038/s41467-025-67142-4.

Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.

Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancer-regulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pre-tumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.

PMID: 41413044 [Indexed for MEDLINE]

5. Redox Biol. 2025 Dec;88:103928. doi: 10.1016/j.redox.2025.103928. Epub 2025 Nov 11.

Loss of NLN suppresses lung cancer progression by inducing ferroptosis through downregulating m(6)A methylation of GPX4.

Current targeted therapies for non-small cell lung cancer (NSCLC) face significant limitations, primarily due to the small proportion of patients who respond to existing targets and the development of drug resistance. Consequently, identifying novel therapeutic targets is crucial to overcome these challenges. In this study, we identified Neurolysin (NLN) as a novel therapeutic target for NSCLC using high-throughput proteomics. We validated the oncogenic role of NLN through in vitro cellular models and in vivo studies, and uncovered a previously unrecognized mechanism in ferroptosis regulation. We demonstrated that NLN expression was significantly upregulated in lung cancer tissues relative to adjacent normal tissues. More notably, inhibition of NLN induced ferroptosis in lung cancer cells. In vivo studies confirmed that the suppression of NLN significantly inhibited tumor growth in a mouse model. Mechanistic investigations revealed that NLN inhibition reduced the m6A modification of GPX4 mRNA, resulting in its degradation and the subsequent induction of ferroptosis. Moreover, we developed a specific small molecule inhibitor, NR2, which targets NLN and induces tumor cell death both in vitro and in vivo, showcasing potent anti-tumor activity. These findings not only establish NLN as a crucial regulator of ferroptosis in NSCLC but also provide a novel therapeutic strategy to target ferroptosis in lung cancer. Our work offers a scientific foundation for the clinical development of NLN-targeted therapies in NSCLC, addressing both the challenges of drug resistance and tumor progression.

PMID: 41242017 [Indexed for MEDLINE]

6. Signal Transduct Target Ther. 2025 Dec 1;10(1):391. doi: 10.1038/s41392-025-02471-w.

Integrative analysis of non-small cell lung cancer identifies Jumonji domain-containing 6/ETS homologous factor axis as a target to overcome radioresistance.

Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.

PMID: 41320721 [Indexed for MEDLINE]

7. Cancer Commun (Lond). 2025 Dec;45(12):1739-1754. doi: 10.1002/cac2.70078. Epub 2025 Nov 14.

Efficacy and safety of combining bevacizumab and fractionated stereotactic radiotherapy for extensive brain metastases in patients with non-small cell lung cancer: a prospective phase II study (GASTO-1053).

BACKGROUND: The prognosis for non-small cell lung cancer (NSCLC) patients with extensive brain metastases (BMs) treated with radiotherapy alone remains poor. Based on the synergistic potential of radiotherapy and angiogenesis inhibitors, we initiated this phase II study to assess the efficacy and safety of combining bevacizumab (Bev) with fractionated stereotactic radiotherapy (FSRT) in managing extensive BMs in NSCLC patients who had stable extracranial disease.

METHODS: Patients with extensive BMs from NSCLC, deemed unsuitable for stereotactic radiosurgery, were prospectively enrolled following multidisciplinary tumor board evaluation. Patients received FSRT (40 Gy in 10 fractions or 30 Gy in 5 fractions) in combination with Bev (7.5 mg/kg on day 1 prior to FSRT and on day 21 post-FSRT). The primary endpoint was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival, progression-free survival, quality of life (QOL), and toxicities. For comparison, NSCLC patients with extensive BMs treated with whole-brain radiotherapy (WBRT) plus FSRT or FSRT alone were matched 1:1 with the study group (Bev + FSRT) using the propensity score matching.

RESULTS: One hundred and six patients were included in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The median IPFS was 18.3 months (95% confidence interval, 15.2-23.3 months). The Bev + FSRT group showed a significant improvement in IPFS compared to both the WBRT + FSRT group (9.6 months, P < 0.001) and the FSRT alone group (8.9 months, P < 0.001). Treatment was well tolerated, with grade 1 radiation necrosis in 1 patient. Bev + FSRT treatment significantly reduced tumor volume (P < 0.001), peritumoral edema volume (P = 0.004), and vascular leakage (P < 0.001). Furthermore, QOL was significantly improved after Bev + FSRT treatment, particularly in patients with symptomatic extensive BMs.

CONCLUSION: These findings support the combination of Bev and FSRT as a safe and effective treatment strategy for extensive BMs in NSCLC patients, offering improved intracranial disease control and symptom relief while avoiding the neurotoxicity associated with WBRT. A randomized trial is warranted to validate the findings of the current study.

PMID: 41235462 [Indexed for MEDLINE]

8. 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]

9. Adv Sci (Weinh). 2025 Dec;12(46):e08245. doi: 10.1002/advs.202508245. Epub 2025 Sep 23.

Repurposing Cardiac Glycosides to Potentiate CD47 Blockade through Calreticulin-mediated Phagocytic Effects for Lung Cancer Treatment.

The abundance of macrophages within the tumor microenvironment (TME) of lung cancer represents a noteworthy therapeutic target. Exploiting the phagocytic function of macrophages by blocking the "don't eat me" signal, CD47, has shown significant therapeutic potential. However, novel CD47-targeted combination strategies warrant further investigation. Through an analysis of data obtained from a screening model focused on the macrophage-mediated killing effect, two cardiac glycosides (CGs), ouabain and digoxin, are shown to increase the capacity of macrophages to kill cancer cells after combination with CD47 antibody. Compared with the control, the combination strategy reduced the tumor volume in different lung cancer models and increased the macrophage phagocytosis rate ≈5-fold. Mechanistically, in addition to Fc-FcγR interaction, CGs enhanced the expression of a pro-phagocytotic signal, calreticulin (CRT). Moreover, PERK inhibitor, ER-Golgi protein trafficking inhibitor, and siRNA-mediated knockdown of exocytosis protein exo70, abrogated both CGs-induced CRT upregulation and the ensuing enhancement of phagocytosis. These findings indicate that CGs drive CRT translocation originates from ER to Golgi apparatus, where it subsequently anchors to the cell surface via exo70-mediated exocytosis. Overall, this study offers compelling evidence that supports the clinical translation of an innovative combination regimen for the treatment of patients with lung cancer.

PMID: 40985476 [Indexed for MEDLINE]

10. Nat Commun. 2025 Dec 16;17(1):7. doi: 10.1038/s41467-025-66334-2.

Cancer stage at diagnosis by duration of pre-existing chronic analgesic use and anxiety or depression.

Pre-existing chronic diseases may delay or expedite cancer diagnosis. Here, we examine variations in cancer stage at diagnosis based on duration and type of common chronic conditions. We identify lung and colon cancers diagnosed 2012-2018 from national cancer registration, and pre-existing physical and mental-health conditions from linked primary care records. Using multivariable logistic regression, we explore associations between the most prevalent conditions (Anxiety/Depression and Chronic Analgesic Medication use), classified as "Recent-onset" (first recorded<12months pre-cancer) or "Persistent/Historic" (12-72 months pre-cancer), and cancer stage at diagnosis. We show that recent-onset Analgesic Medication use can be associated with increased odds of advanced stage lung or colon cancer diagnosis. Conversely, persistent/historic Chronic Analgesic Medication use can be associated with reduced odds of advanced stage lung cancer and persistent/historic Anxiety/Depression with reduced odds of advanced stage lung or colon cancer. Persistent or historic conditions may increase healthcare utilisation, offering opportunities for early cancer diagnosis. Recent-onset conditions may lead to delays through the alternative explanations or competing demands mechanisms.

PMID: 41402270 [Indexed for MEDLINE]

11. J Thorac Oncol. 2025 Dec;20(12):1791-1800. doi: 10.1016/j.jtho.2025.08.005. Epub 2025 Aug 9.

Tumor Cell Invasion of the External Elastic Lamina Designates Visceral Pleural Invasion and Predicts Poorer Patient Outcomes in Pulmonary Nonmucinous Invasive Adenocarcinoma.

INTRODUCTION: Visceral pleural invasion (VPI) of lung cancer is defined as involvement by tumor cells into the elastic laminae of the visceral pleura. In both the American Joint Committee on Cancer staging system and the College of American Pathologists cancer protocol, VPI is classified as follows: PL-0 for tumors that do not invade the elastic lamina; PL-1 for tumors that invade the elastic lamina but not up to the pleural surface; PL-2 for tumors that invade up to the pleural surface without involvement of adjacent anatomic structures; and PL-3 for tumors that invade the parietal pleura. Staging of tumors smaller than 3 cm in size will be upgraded from T1 to T2 if VPI (PL-1 or PL-2) is present. Currently, it is recommended that tumor cells invading the outmost (external or outer) elastic lamina, rather than the internal or inner elastic lamina, serve as the criterion for diagnosing VPI. Nevertheless, there is scarce evidence supporting this widely adopted recommendation. Real-world experiences are needed to further validate the clinical significance of lung cancer invading the external versus internal elastic lamina of the visceral pleura.

METHODS: We retrospectively reviewed the clinicopathologic characteristics of 1217 patients with lung cancer with surgically resected nonmucinous invasive adenocarcinoma between 2011 and 2016. Using the scheme with two-layered elastic laminae, VPI was categorized into PL-n (no pleural invasion; tumor involvement beneath the internal elastic lamina), PL-i (tumor invading into or beyond the internal elastic lamina and beneath the external elastic lamina), PL-e (tumor invading into or beyond the external elastic lamina but not reaching the parietal pleura), and PL-p (tumor invading through the elastic laminae and reaching the parietal pleura). We analyzed the relationship between categories of VPI and prognosis, along with other pertinent clinical and histopathologic parameters.

RESULTS: The 5-year overall survival rates were 89.7% for patients with PL-n, 89.5% for PL-i, 71.3% for PL-e, and 53.3% for PL-p, whereas the 5-year recurrence-free survival rates were 88.1%, 85.8%, 55.8%, and 48.6%, respectively. PL-e demonstrated significant differences in univariate analyses in the overall survival analysis, whereas in the disease-free survival analysis, PL-e demonstrated significant differences in both univariate and multivariate analyses.

CONCLUSIONS: The tumor cell invading the external elastic lamina (PL-e) was a significant prognostic factor for recurrence and associated with worse overall survival for pulmonary nonmucinous invasive adenocarcinoma, compared with the tumor cell invading beneath the external elastic lamina (PL-i). This study provides evidence supporting the use of the outmost external elastic lamina involvement as the landmark of visceral pleural invasion in current clinical practice.

PMID: 40789389 [Indexed for MEDLINE]

12. J Control Release. 2025 Dec 10;388(Pt 1):114348. doi: 10.1016/j.jconrel.2025.114348. Epub 2025 Oct 21.

Enhancing cisplatin therapy for small cell lung cancer via a dual strategy of combining surufatinib and CD47 blockade.

Small cell lung cancer (SCLC) is a highly lethal malignancy with a < 7 % 5-year survival rate. Platinum-based chemotherapy remains the standard treatment; however, its clinical efficacy is limited. There is an urgent need for new therapeutic strategies. In this study, we developed a RGD labeled liposome (CS/RGD-Lipo) encapsulating both cisplatin and surufatinib as a target delivery system against SCLC, aimed at enhancing ferroptosis to improve cisplatin efficacy, inhibiting angiogenesis, and reversing TAM phenotypes to overcome immunosuppression. Additionally, we combined CS/RGD-Lipo with αCD47 to further enhance antitumor activity. In tumor-bearing mice, CS/RGD-Lipo effectively targeted tumor tissues for the delivery of cisplatin and surufatinib. The combination of CS/RGD-Lipo with αCD47 significantly promoted ferroptosis in SCLC, improved anti-angiogenesis, induced the conversion of M2 macrophages to M1 macrophages, and enhanced the M1 macrophages-mediated antitumor immune response, resulting in a marked inhibition of tumor growth in SCLC mouse models. Taken together, this work demonstrates a feasible therapeutic approach to inhibit SCLC by combining cisplatin, surufatinib, and αCD47 to leverage tumor ferroptosis, angiogenesis inhibition and tumor-associated macrophage polarization.

PMID: 41130421 [Indexed for MEDLINE]

13. Cancer Res. 2025 Dec 15;85(24):5141-5160. doi: 10.1158/0008 5472.CAN-25-1407.

Large-Scale T-cell Receptor Repertoire Profiling Unveils Tumor-Specific Signals for Diagnosing Indeterminate Pulmonary Nodules.

Indeterminate pulmonary nodules (IPN) are increasingly detected due to increasing health awareness and widespread lung cancer screening, yet distinguishing benign from malignant nodules remains a critical challenge. Emerging evidence suggests that recognizing cancer-associated immune signatures represents a powerful approach for early-stage cancer detection. This study explored the clinical utility of T-cell receptor (TCR) repertoire analysis in IPN evaluation. By conducting large-scale TCR sequencing (6,059 blood and 988 tumor samples), we established LungTCR (https://www.lungtcr.com/), a comprehensive TCR repertoire database, and proposed a method for the quantitative assessment of tumor-related immune responses. LungTCR was leveraged to develop TCRnodseek plus, a diagnostic model integrating clinical data, CT imaging, and TCR features. A multicenter prospective study (ChiCTR2200055761) involving 1,107 patients with IPN validated the superior diagnostic performance of TCRnodseek plus over existing approaches. Mechanistic analyses revealed that the identified lung cancer-related TCR clones are enriched in non-small cell lung cancer and are predominantly present in malignant nodules and tumor tissues. This study provides a robust TCR database and an advanced diagnostic model, offering a framework for precise IPN differentiation.

SIGNIFICANCE: Construction of the largest TCR database of lung nodules enabled identification of lung cancer-specific TCR sequences and development of an advanced machine learning model to distinguish benign from malignant pulmonary nodules.

PMID: 41150899 [Indexed for MEDLINE]

14. Trends Cancer. 2025 Dec;11(12):1134-1136. doi: 10.1016/j.trecan.2025.10.007. Epub 2025 Nov 12.

IL17-producing γδ T cells promote radioresistance via immunosuppression.

IL17-secreting γδ T cells promote immunosuppression, metastatic dissemination, and resistance to treatment in various oncological settings. Recent findings from Deng et al suggest that DNA-containing extracellular vesicles released from irradiated lung cancer cells favor radioresistance by orchestrating the recruitment of IL17-secreting γδ T cells via a CCL20-dependent mechanism involving STING signaling in tumor-associated macrophages.

PMID: 41233192 [Indexed for MEDLINE]

15. Sci Adv. 2025 Dec 5;11(49):eady7032. doi: 10.1126/sciadv.ady7032. Epub 2025 Dec 5.

Steric disruption of EGFR oligomerization overcomes therapy resistance in non-small cell lung cancer.

Acquired drug resistance mutations in epidermal growth factor receptor (EGFR) present a substantial clinical challenge in treating non-small cell lung cancer (NSCLC). While EGFR oligomerization plays a pivotal role in modulating receptor signaling, its relationship with resistance mutations remains unclear. Here, we investigated the real-time link between oligomerization of oncogenic and resistant EGFR mutants and downstream signaling using a fluorescent protein-based proximity probe and signaling reporter in living cells. We found that EGFR mutants resistant to tyrosine kinase inhibitors (TKIs) exhibited higher oligomerization than did wild-type EGFR with or without EGF. The efficacy of TKIs and allosteric drugs inversely correlated with receptor oligomerization. Furthermore, sterically disrupting EGFR oligomerization by genetically fusing a bulky protein to resistant mutants overcame resistance and suppressed proliferation. Moreover, extracellular application of bulky EGFR binders suppressed resistant mutants by disrupting oligomerization. These findings highlight steric disruption of EGFR oligomerization as a promising strategy for overcoming therapy resistance in NSCLC and introduce a versatile screening platform for developing competitive and allosteric inhibitors.

PMID: 41348890 [Indexed for MEDLINE]

16. Signal Transduct Target Ther. 2025 Dec 24;10(1):417. doi: 10.1038/s41392-025-02514-2.

Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer.

Brain metastasis is a major contributor to mortality in patients with lung cancer. The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1β, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung cancer.

PMID: 41436606 [Indexed for MEDLINE]

17. Carbohydr Polym. 2025 Dec 1;369:124288. doi: 10.1016/j.carbpol.2025.124288. Epub 2025 Aug 25.

Structure characterization of a polysaccharide isolated from sugarcane leaves and its macrophage polarization activity and beneficial effects for cisplatin treatment of lung cancer.

Polysaccharides with immunomodulatory functions have drawn increasing attention in cancer immunotherapy. A bioactive polysaccharide, SLP-D2N2, was extracted from the sugarcane (Saccharum sinensis Roxb.) leaves. Structural analysis suggested that the core region of SLP-D2N2 is likely composed primarily of →4)-β-D-xylose-(1→, with a smaller amount of →3,4)-α-D-xylose-(1→. Side chains connect to the O → 3 site of the sugar unit →3,4)-α-D-xylose-(1 → via α-L-arabinofuranose-(1→. SLP-D2N2 significantly promoted macrophage proliferation, enhanced phagocytosis and increased production of TNF-α and IL-6. Flow cytometry indicated that SLP-D2N2 inhibited M2 macrophage polarization while promoting M1 macrophage polarization. When combined with cisplatin, SLP-D2N2 enhanced the drug sensitivity of A549-luc lung cancer cells. SLP-D2N2 was found to stimulate the TLR4 signaling pathway to induce macrophage polarization toward the M1 type, thereby facilitating synergistic anti-tumor effects. In a lung cancer mouse model established with A549-luc cells, SLP D2N2 increased M1 macrophage polarization and augmented immune activity. When administered alongside cisplatin, SLP-D2N2 exhibited substantial synergistic anti-tumor effects while reducing the cardiotoxicity and nephrotoxicity typically associated with cisplatin treatment. These findings advance the expanding field of research on bioactive polysaccharides and their roles in cancer immunotherapy.

PMID: 40973256 [Indexed for MEDLINE]

18. J Control Release. 2025 Dec 10;388(Pt 1):114299. doi: 10.1016/j.jconrel.2025.114299. Epub 2025 Oct 9.

Polymeric-lipid nanoparticles that leverage cationic helper lipids and the protein corona for lung-targeted delivery of a novel anti-cancer drug.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for more effective therapeutic strategies. Nanomedicine offers a promising avenue to improve treatment outcomes by enabling localised drug delivery within the lungs. Drawing inspiration from the recent success of mRNA lipid nanoparticles, we developed a novel class of polymeric-lipid nanoparticles (P-LNPs) designed to encapsulate RB-012, an anticancer compound that inhibits 14-3-3 protein function but is rapidly cleared from systemic circulation due to its cationic and amphiphilic properties. RB-012 was co-assembled with the anionic polymer polyacrylic acid (PAA) and various combinations of cholesterol, pegylated, and charged helper lipids to form stable P-LNPs that significantly impeded in vitro premature drug release. This approach resulted in >30-fold increase in bioavailability following intravenous administration (2 mg/kg) to Sprague-Dawley rats. Varying the helper lipid composition, through the inclusion of 16-32 mol% of the cationic lipid, DOTAP, yielded a > 50-fold increase in pulmonary drug exposure compared to unformulated RB-012. These biodistribution enhancements were linked to altered protein corona profiles on the nanoparticle surface, with P-LNPs formulated with DOTAP increasing the degree of protein corona adsorption in a concentration-dependent manner, compared to P-LNPs prepared with the anionic helper lipid, DOPE. In vitro and in ovo assays confirmed that the P-LNPs significantly improved the anti-tumour efficacy of RB-012, supporting their potential as a targeted therapeutic platform for lung cancer treatment.

PMID: 41067600 [Indexed for MEDLINE]

19. Nat Commun. 2025 Dec 9;16(1):10983. doi: 10.1038/s41467-025-66800-x.

ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer.

Small cell lung cancer (SCLC) is characterized by its highly aggressive phenotype and dismal outcome. Despite the benefit of adding immune checkpoint blockade to standard chemotherapy, tumors acquire the ability to evade immunosurveillance and develop resistance. To investigate these underlying mechanisms, we perform high-dimensional profiling of human and murine SCLC specimens. In matched primary and metastatic human samples, we observe MHC-I loss in metastases, highlighting its role in immune evasion. Correspondingly, silencing MHC-I in SCLC cells drastically reduces immune infiltration and promotes metastasis in mice. Using mass spectrometry and phospho-tyrosine kinase analyses, we identify ERBB2 signaling as a suppressor of MHC-I and driver of immune-modulatory transcripts. Mechanistically, genetic and pharmacologic blockade of ERBB2 induces MHC-I in a STING-dependent manner and prevents immune evasion in autochthonous murine SCLC. Strikingly, combining ERBB2 inhibition with anti-PD-1 elicits profound synergistic responses in preclinical models, suggesting this combination for future clinical trials in SCLC patients.

PMID: 41361170 [Indexed for MEDLINE]

20. J Thorac Oncol. 2025 Dec;20(12):1801-1813. doi: 10.1016/j.jtho.2025.07.114. Epub 2025 Jul 22.

The 2024 International Association for the Study of Lung Cancer Global Survey on Biomarker Testing.

INTRODUCTION: Biomarker status is vital to inform optimal care for individuals with lung cancer, yet implementation of testing has been suboptimal due to cost, lack of quality and standards, access, awareness, and long turnaround times. Recent therapeutic advances in late- and early-stage lung cancers motivated a second global survey on comprehensive biomarker testing in 2024.

METHODS: The International Association for the Study of Lung Cancer convened a global multidisciplinary committee to develop the survey. We used a mixed methods framework, with qualitative focus groups and in-depth interviews informing the primarily quantitative survey. The survey was available in six languages.

RESULTS: We received 1677 responses across 90 countries and 14 disciplines. Respondents believe that biomarker testing significantly affects outcomes (98.3%) and have a clear understanding of who should receive testing (91.2%). Nevertheless, only 63.4% and 29.4% ranked it highly important to perform comprehensive biomarker testing in late- and early-stage lung cancer, respectively. Many respondents (67%) estimated that more than half of individuals with lung cancer are biomarker tested in their country, up from 39% in the 2018 survey (p value < 0.0001). Nevertheless, 43% of the respondents sometimes or often treat patients before receiving biomarker results. The highest ranked barriers were cost (27.2%), time (13.9%), sample quality (13.8%), access (12.8%), and awareness (8.0%). We found that the health care system support for biomarker testing varied by country-level income.

CONCLUSIONS: We found improvements in the perception of testing rates compared with that in 2018, but continued and substantial barriers exist. Future initiatives will use these data to target awareness, access, processes, and policy initiatives to improve comprehensive testing globally.

PMID: 40706709 [Indexed for MEDLINE]

21. Cancer Res. 2025 Dec 1;85(23):4806-4824. doi: 10.1158/0008-5472.CAN-24-4887.

Loss of UXS1 Selectively Depletes Pyrimidines and Induces Replication Stress in KEAP1-Mutant Lung Cancer.

Kelch-like ECH-associated protein 1 (KEAP1) is the third most commonly mutated gene in non-small cell lung cancer and is associated with poor prognosis. In this study, we investigated synthetic lethal interaction genes in KEAP1-mutated cancer cells and identified a dependency on UDP-xylose synthase 1 (UXS1), which converts UDP-glucuronic acid (UDP-GlcA) to UDP-xylose in the proteoglycan synthetic pathway. UDP-glucose dehydrogenase (UGDH), a transcriptional target of NRF2 that converts UDP-glucose to UDP-GlcA, was highly expressed in KEAP1-mutant tumors. Upon UXS1 knockdown, depletion of UDP-xylose occurred in both KEAP1-mutant and wild-type cells, whereas UDP-GlcA accumulated to a greater extent in the KEAP1-mutant setting. The resulting shortage of available UDP and other pyrimidines slowed S-phase progression and stalled DNA replication fork marks, causing cells to undergo prolonged cell-cycle exit or apoptosis. Dependency on UXS1 was rescued by knocking out UGDH to prevent UDP-GlcA accumulation and UDP depletion. DNA replication stress in UXS1-depleted cells sensitized them to clinical cell-cycle checkpoint inhibitors. Furthermore, CRISPR screening experiments identified genes that modulate UXS1 dependency. Whereas the liver had the highest normal tissue expression of UGDH, UXS1 knockout in the liver did not result in hepatotoxicity. Taken together, these data demonstrate that UXS1 is a selective dependency in KEAP1-mutant tumors, and loss of UXS1 creates additional therapeutically exploitable vulnerabilities in KEAP1-mutant tumors.

SIGNIFICANCE: UXS1 loss in KEAP1-mutant cells causes pyrimidine nucleotide depletion, DNA replication stress induction, and ultimately cell-cycle exit that results in tumor stasis, highlighting UXS1 as a potential therapeutic target in KEAP1-mutant tumors. See related commentary by Yasseen and DeNicola, p. 4582.

PMID: 40966319 [Indexed for MEDLINE]

22. Adv Sci (Weinh). 2025 Dec;12(48):e08481. doi: 10.1002/advs.202508481. Epub 2025 Oct 21.

Smohaze-Upregulated RFWD3 Competes with TRIM24 to Stabilize TREX1 and Reduce Cytosolic dsDNA in Non-Small Cell Lung Cancer.

The three-prime repair exonuclease 1 (TREX1), an intracellular double-stranded DNA (dsDNA) degrader that inhibits the stimulator of interferon (IFN) genes (STING) pathway, is turned over by E3 ligase TRIM24-mediated proteasomal degradation. To uncover TREX1-stabilizers in non-small cell lung cancer (NSCLC), mass spectrometry is conducted, and 374 candidates are identified, with the RING Finger and WD Repeat Domain 3 (RFWD3) as a TREX1 protector that sequesters it from TRIM24. Overexpression of RFWD3 promotes tumor growth with increased myeloid-derived suppressor cells (MDSCs), while inhibition of RFWD3 increases intracellular dsDNA levels, activates the STING-IFN signaling, decreases MDSCs, and enhances the efficacy of PD-L1 blockade in murine NSCLC models. Furthermore, smoker patients have higher RFWD3 levels than non-smoker patients, and cigarette smoke extract, PM2.5, and benzo(a)pyrene upregulatesRFWD3 via transcription factor aryl hydrocarbon receptor. These results indicate a role of RFWD3 in tobacco smoke and haze (smohaze)-promoted immune evasion, inhibition of which activates STING-IFN signaling and synergizes with immune checkpoint inhibitors in NSCLC.

PMID: 41117130 [Indexed for MEDLINE]

23. J Thorac Oncol. 2025 Dec;20(12):1763-1777. doi: 10.1016/j.jtho.2025.07.121. Epub 2025 Jul 25.

Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.

METHODS: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).

RESULTS: We analyzed 4841 patients including 165 PSC cases treated with ICI-based therapy from three institutions and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1138 (75.1%) LUAD, and 312 (20.6%) LUSC. Patients with PSC were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for patients with PSC compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37% to 43% of patients with PSC who received ICIs were responders, compared with 26% to 29% in LUAD and 22% to 46% in LUSC (p < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared with LUAD or LUSC and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared with LUAD. Case observation revealed relatively better outcomes to ICI than targeted therapies in patients with PSC with MET exon 14 skipping or KRAS G12C.

CONCLUSION: PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.

PMID: 40716572 [Indexed for MEDLINE]

24. Cancer Discov. 2025 Dec 2;15(12):2554-2573. doi: 10.1158/2159-8290.CD-24-1565.

Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes.

Update of

    bioRxiv. 2024 Aug 20:2024.08.19.607671. doi: 10.1101/2024.08.19.607671.

Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We used a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic Kras-driven lung tumors. We identified many previously unappreciated epigenomic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by the HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, affect chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo.

SIGNIFICANCE: Using a novel functional genomics method in vivo, we investigated epigenomic regulators in lung tumorigenesis. We discovered multiple novel genes that affect tumor growth. We show that the HBO1 and MLL1 complexes interact to suppress lung adenocarcinoma. Our findings provide broad insights into the epigenomic regulatory landscape of lung cancer.

PMID: 40997327 [Indexed for MEDLINE]

25. Nat Commun. 2025 Dec 8;16(1):10939. doi: 10.1038/s41467-025-65930-6.

Precise diagnosis of small invasive pulmonary nodules driven by single-cell immune signatures in peripheral blood.

Early detection of lung cancer is crucial for improving patient outcomes. However, accurately diagnosing invasive pulmonary nodules and predicting tumor invasiveness remain major clinical challenges. Given the established role of immune dysfunction in cancer development, we hypothesize that peripheral immune profiling could provide a strategy for managing pulmonary nodules. In this multi-center, prospective study, we combine peripheral immune profiling via mass cytometry with machine learning algorithms to develop an integrated pulmonary nodule management platform. This platform accurately distinguishes invasive from non-invasive pulmonary nodules (AUC = 0.952), outperforming established clinical and radiomics-based models. Furthermore, it effectively predicts tumor invasiveness, differentiating minimally invasive from invasive adenocarcinoma (AUC = 0.949), thereby offering valuable guidance for surgical decision-making. In conclusion, the platform demonstrates substantial clinical utility and holds significant promise as a precision tool for future management of pulmonary nodules.

PMID: 41360981 [Indexed for MEDLINE]

26. J Thorac Oncol. 2025 Dec;20(12):1778-1790. doi: 10.1016/j.jtho.2025.07.131. Epub 2025 Aug 5.

Digital Versus Manual PD-L1 Scoring in Advanced NSCLC From the IMpower110 and IMpower150 Trials.

INTRODUCTION: Treatment selection in patients with advanced NSCLC is based on programmed death-ligand 1 (PD-L1) expression, which is usually scored manually and is subject to intra- and inter-pathologist variability. A PD-L1 clone-agnostic artificial intelligence (AI) model for AI-based measurement of PD-L1 (AIM-PD-L1) was developed and assessed in advanced NSCLC using clinical samples from two phase 3 trials.

METHODS: IMpower110 evaluated atezolizumab versus chemotherapy in PD-L1-positive metastatic, stage IV, squamous or nonsquamous NSCLC. IMpower150 evaluated atezolizumab, carboplatin, and paclitaxel, with or without bevacizumab, versus carboplatin, paclitaxel, and bevacizumab in patients with metastatic nonsquamous NSCLC. AIM-PD-L1 was developed and deployed on SP263-stained whole slide images (IMpower110, n = 509; IMpower150, n = 766) for digital scoring of tumor cell (TC) PD-L1 expression and identification of human-interpretable features (HIFs) associated with survival outcomes.

RESULTS: Overall percentage agreements between scoring methods for TC more than or equal to 50% and more than or equal to 1% cutoffs were high. Survival analyses were similar for PD-L1 subgroups between scoring methods at both TC cutoffs. A nonsignificant improvement in survival outcomes was observed in patients treated with atezolizumab-containing regimens and classified as positive by digital scoring but missed by manual scoring. Two HIFs in the cancer epithelium-density of all PD-L1-positive TC and immune cells-were nominally associated with overall survival. Many HIFs were identified to be predictive of significantly improved progression-free survival with atezolizumab-containing regimens versus control.

CONCLUSIONS: AIM-PD-L1 digital SP263 PD-L1 scoring is concordant with manual scoring, revealing similar predictivity for benefit, and could potentially be used as a predictive marker for patient stratification and selection for anti-PD-(L)1 therapy.

PMID: 40759194 [Indexed for MEDLINE]

27. Lancet Planet Health. 2025 Dec;9(12):101334. doi: 10.1016/j.lanplh.2025.101334. Epub 2025 Dec 8.

Long-term exposure to PM(2·5) constituents and incident cancer among Medicare beneficiaries in the USA: a national cohort study.

BACKGROUND: The health burden from cancer has markedly increased over the past 20 years. Total PM2·5 has been identified as an environmental risk factor for cancer. However, how each constituent of PM2·5 contributes to the development of cancer is largely unknown. We aimed to investigate the association between 15 PM2·5 constituents, sources of PM2·5, and the incidence of five common cancers among adults aged 65 years and older in the USA.

METHODS: For this national cohort study, we included beneficiaries of Medicare in the USA, aged 65 or older, who were followed for various time periods between Jan 1, 2000, and Dec 31, 2018. The concentrations of 15 PM2·5 constituents in the contiguous USA were estimated using ensemble machine learning models, and the sources of PM2·5 were identified from the PM2·5 constituent data using non-negative matrix factorisation. The outcomes were incident lung, colorectal, prostate, breast, and endometrial cancers, for which information was extracted from the Medicare Chronic Conditions Data Warehouse database. Associations between PM2·5 constituents and the outcomes were investigated using a generalised weighted-quantile sum regression model with the Cox-approximate Poisson method, and associations between PM2·5 sources and outcomes were investigated using Cox-approximate Poisson regression models.

FINDINGS: 15 138 652 Medicare beneficiaries were included in the study, with a median follow-up period of 9 years (IQR 5-15). The incidences per 1000 person-years were 15·9 for lung cancer, 18·9 for colorectal cancer, 73·5 for prostate cancer, 50·7 for breast cancer, and 11·4 for endometrial cancer. Each one-decile increase in exposure to the PM2·5 mixture was associated with incident rate increases of 6·4% (95% CI 5·9 to 6·9) for lung cancer, 4·3% (3·8 to 4·8) for colorectal cancer, 3·6% (3·1 to 3·9) for prostate cancer, and 2·0% (1·7 to 2·4) for breast cancer. No association was observed for endometrial cancer (0·4% [-0·4 to 1·1]). Of the PM2·5 constituents, vanadium contributed the largest relative weight in the observed associations (ranging from 23·7-36·1%). Increased incidence of all five cancers was associated with PM2·5 sourced from fuel oil combustion (14·1% [95% CI 6·5-22·3] for lung cancer, 15·6% [7·5-24·2] for colorectal cancer, 18·4% [5·2-33·4] for prostate cancer, 9·2% [7·9-10·5] for breast cancer, and 5·6% [2·9-8·3] for endometrial cancer for each 1 μg/m3 increase in concentration) and with PM2·5 sourced from coal combustion (6·9% [3·3-10·7] for lung cancer, 9·2% [6·6-11·9] for colorectal cancer, 7·3% [3·6-11·1] for prostate cancer, 6·2% [3·2-9·3] for breast cancer, and 3·3% [2·2-4·3] for endometrial cancer).

INTERPRETATION: PM2·5 exposure was associated with an increased risk of cancer, with vanadium-a marker of fuel oil combustion-contributing the largest weight in the observed association. Future PM2·5 regulations should consider targeting the constituents and sources that have the largest health effects.

FUNDING: National Institutes of Health.

PMID: 41380707 [Indexed for MEDLINE]

28. Lancet Oncol. 2026 Jan;27(1):36-44. doi: 10.1016/S1470-2045(25)00594-7. Epub 2025 Dec 6.

Vebreltinib in MET amplification-driven advanced non-small-cell lung cancer (KUNPENG): a single-arm, multi-cohort, multicentre, phase 2 study.

BACKGROUND: MET amplification is recognised as a de novo driver alteration in non-small-cell lung cancer (NSCLC) but treatment responses with existing MET inhibitors remain largely unsatisfactory. We aimed to investigate the antitumour activity and safety of vebreltinib, a potent and highly selective MET inhibitor,in patients with MET amplification-driven NSCLC.

METHODS: KUNPENG was a multicentre, multi-cohort, single-arm, phase 2 trial conducted across 17 hospitals in China, in patients with locally advanced or metastatic NSCLC with MET dysregulation. Patients were eligible if they were MET inhibitor-naive, aged 18 years or older with MET amplification-driven NSCLC (gene copy number of six or higher), and progressed after previous standard chemotherapy or were ineligible for chemotherapy (cohort 2) or refused chemotherapy (cohort 3). Patients received 200 mg vebreltinib orally twice daily until disease progression or intolerable toxicity. The primary endpoint was the objective response rate, assessed by a masked independent review committee in the full analysis set. The study was amended to merge cohorts 2 and 3 due to slow accrual and was closed to enrolment on Nov 14, 2023. This trial is registered with ClinicalTrials.gov (NCT04258033).

FINDINGS: Between Jan 17, 2020, and Nov 14, 2023, 145 patients were enrolled; of these, 86 patients (30 chemotherapy-treated and 56 untreated) from cohorts 2 and 3 were included in the current analysis. The median age was 65 years (range 48-82; IQR 59-71), 77 (90%) patients were male, and nine (10%) were female. All patients were Chinese. 42 patients had partial response, resulting in an objective response rate of 48·8% (42 of 86; 95% CI 38·3-59·4) per masked independent review committee. The median follow-up was 18·6 months (IQR 15·7-37·3). The incidence of grade 3 or worse treatment-related adverse events was 31% (27 of 86), predominantly abnormal liver function terms reported by the investigators (eight [9%]). Serious adverse events related to treatment were reported by 16 (19%) patients. 11 treatment-emergent adverse events leading to death occurred, of which one patient died of abnormal liver function, which was possibly related to vebreltinib treatment.

INTERPRETATION: Vebreltinib showed antitumour activity in patients with MET amplification-driven advanced NSCLC who had previously received chemotherapy or were chemotherapy-naive. Further research is needed to validate these findings.

FUNDING: Beijing Pearl Biotechnology and Avistone Biotechnology.

PMID: 41365311 [Indexed for MEDLINE]

29. J Clin Oncol. 2026 Jan;44(1):54-65. doi: 10.1200/JCO-24-02835. Epub 2025 Dec 1.

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non-Small Cell Lung Cancer: Results From CHRYSALIS-2.

PURPOSE: For patients with advanced non-small cell lung cancer (NSCLC) harboring atypical epidermal growth factor receptor (EGFR) mutations (eg, S768I, L861Q, G719X), efficacy of current treatment options is limited.PATIENTS AND METHODS: CHRYSALIS-2 Cohort C enrolled participantswith NSCLC harboring atypical EGFR mutations (G719X, S768I, L861Q, etc) and ≤2 previous lines of therapy. Participants were treatment-naïve or previously received first- or second-generation EGFR tyrosine kinase inhibitors. Coexisting exon 20 insertions, exon 19 deletions, or exon 21 L858R mutations were exclusionary. Participants received 1,050 mg (1,400 mg if ≥80 kg) intravenous amivantamab once weekly for the first 4 weeks and then once every 2 weeks plus 240 mg oral lazertinib once daily. The primary end point was investigator-assessed objective response rate (ORR).

RESULTS: As of January 12, 2024, 105 participants received amivantamab-lazertinib. Most common atypical mutations were G719X (56%), L861X (26%), and S768I (23%), including single and compound mutations. In the overall population (median follow-up: 16.1 months), the ORR was 52% (95% CI, 42 to 62). The median duration of response (mDoR) was 14.1 months (95% CI, 9.5 to 26.2). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.8 to 17.8); median overall survival (mOS) was not estimable (NE; 95% CI, 22.8 to NE). Adverse events were consistent with previous studies and primarily grade 1 and 2. Among treatment-naïve participants, the ORR was 57% (95% CI, 42 to 71). The mPFS was 19.5 months (95% CI, 11.2 to NE), the mDoR was 20.7 months (95% CI, 9.9 to NE), and mOS was NE (95% CI, 26.3 to NE). Solitary or compound EGFR mutations had no major impact on ORR. The ORR in participants with P-loop and αC-helix compressing, classical-like, and T790M-like mutations was 45% (n = 38), 64% (n = 14), and 67% (n = 3), respectively.

CONCLUSION: In participants with atypical EGFR-mutated advanced NSCLC, amivantamab-lazertinib demonstrated clinically meaningful antitumor activity with no new safety signals.

PMID: 41325571 [Indexed for MEDLINE]

30. J Hematol Oncol. 2025 Dec 7;18(1):111. doi: 10.1186/s13045-025-01768-1.

PACIFIC-5: a phase III clinical trial of consolidation durvalumab in patients with unresectable stage III NSCLC and no progression after concurrent or sequential chemoradiotherapy.

BACKGROUND: Consolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT.

METHODS: This randomised, double-blind, placebo-controlled, phase III trial enrolled patients aged ≥ 18 years with unresectable stage III NSCLC, regardless of PD-L1 expression or sensitising EGFR or ALK aberrations, without disease progression after cCRT or sCRT. Patients were randomised (2:1) to durvalumab 1500 mg or placebo intravenously every 4 weeks (stratified by tumour PD-L1 expression and prior treatment) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival (PFS) by blinded independent central review in the modified intention-to-treat population (mITT). Secondary endpoints included overall survival (OS) in the mITT and safety. The safety analysis set include patients who received at least one dose of study treatment.

RESULTS: Of 407 patients randomised to receive durvalumab (n = 272) or placebo (n = 135), 405 received at least one dose of durvalumab (n = 271) or placebo (n = 134). The mITT comprised 381 patients randomised to durvalumab (n = 252) or placebo (n = 129). Durvalumab showed statistically significant improvement in PFS versus placebo in the mITT (median [95% confidence interval {CI}], 14.0 [10.9-18.0] vs. 6.5 [5.4-13.8] months; hazard ratio [95% CI], 0.75 [0.58-0.99]; p = 0.038). There was a trend toward improved OS with durvalumab versus placebo in the mITT (median [95% CI], 38.3 [28.9-42.8] vs. 32.5 [20.6-40.4] months; hazard ratio [95% CI], 0.87 [0.66-1.17]; p = 0.346 [interim analysis]). Among the safety analysis set, maximum grade 3 or 4 adverse events of any cause occurred in 26.9% (73/271) and 23.9% (32/134) and 1.5% (4/271) and 0% (0/134) had treatment-related adverse events leading to death for durvalumab and placebo, respectively.

CONCLUSIONS: PACIFIC-5 met its primary endpoint of improved PFS after either cCRT or sCRT. Follow-up for overall survival is ongoing.

TRIAL REGISTRATION: NCT03706690.

PMID: 41354932 [Indexed for MEDLINE]

31. Adv Sci (Weinh). 2025 Dec;12(48):e06565. doi: 10.1002/advs.202506565. Epub 2025 Nov 25.

Tumor-Informed ctDNA in Guiding First-Line Immunochemotherapy in Advanced Non-Small Cell Lung Cancers.

Predictive biomarkers are urgently needed for first-line immune checkpoint inhibitors plus chemotherapy (ICI-chemo) in advanced non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) reflects tumor burden and immunogenicity, potentially identifyinging of patients suitable for ICI-chemo. In this study, pre- and on - treatment tissue and plasma samples are prospectively collected and analyzed from the randomized phase III CHOICE-01 trial comparing ICI - chemo versus chemotherapy alone in advanced NSCLC. Pre-treatment tissue and plasma samples, as well as on-treatment plasma samples, are prospectively collected. Tumor-informed ctDNA detection is based on tissue-identified mutations. Among patients with tumor-informed ctDNA positivity, those receiving ICI-chemo experienced significantly improved-free survival (PFS) and overall survival (OS) compared to those receiving chemotherapy alone (PFS: HR 0.45, 95% CI 0.34-0.60; OS: HR 0.66, 95% CI 0.49-0.88; p = 0.0045). In contrast, no significant differences in PFS or OS are observed between treatment arms in the ctDNA-negative subgroup. The predictive value of tumor-informed ctDNA is independent of other immune biomarkers and superior to other ctDNA metrics. Validation in a combined cohort from RATIONALE 304/307 trials shows similar results. Furthermore, ctDNA clearance during treatment correlates with better clinical outcomes (log-rank p = 0.0004 for OS and p = 0.044 for PFS).

PMID: 41287887 [Indexed for MEDLINE]

32. Signal Transduct Target Ther. 2025 Dec 2;10(1):393. doi: 10.1038/s41392-025-02481-8.

A prospective, multicenter, comprehensive genomic profile signature study in patients with EGFR-mutant advanced non-small cell lung cancer at the first-line treatment failure of osimertinib.

Osimertinib, the first approved third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), exhibits notable efficacy in EGFR-mutant non-small cell lung cancer (NSCLC). This is a prospective, multicenter, comprehensive genomic profile signature (GPS) study in paired tissue and plasma samples from 149 patients with advanced NSCLCharboring EGFR exon 19 deletion (Ex19del) or L858R mutation at the first-line treatment failure of osimertinib (NCT05219162). Next-generation sequencing (NGS) was used for comprehensive GPS analysis of paired tissue and plasma samples. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used for tissue samples, while droplet digital polymerase chain reaction (ddPCR) and NGS were used for plasma samples to perform a concordance analysis of MET amplification. At the first-line treatment failure of osimertinib (study entry), EGFR alterations in tissue samples included EGFR Ex19del (49.0%, 73/149), EGFR L858R mutation (43.0%, 64/149), EGFR amplification (32.9%, 49/149), EGFR L718Q/V mutation (4.7%, 7/149), and EGFR C797S mutation (3.4%, 5/149); bypass signaling activation and downstream pathway activation alterations included TP53 mutation (69.8%, 104/149) and MET amplification (30.9%, 46/149). Among the 136 patients with EGFR Ex19del/L858R mutation in tissue samples, 72.1% (98/136), 35.3% (48/136), and 32.4% (44/136) had TP53 mutations, EGFR amplification, and MET amplification, respectively. Taking tissue samples as references, the GPS in plasma samples showed high specificity (90.7-100%) for almost all genomic alterations. Compared with FISH (gene copy number [GCN] ≥10), the overall percent agreement of tissue NGS, optimized tissue NGS (GCN ≥ 8.63), plasma NGS, and plasma ddPCR for MET amplification were 75.0% (27/36), 100% (36/36), 88.9% (32/36), and 94.4% (34/36), respectively. This study represents the largest-scale, prospective study with paired tissue and plasma samples to enable comprehensive analysis of GPS, providing a novel perspective into coalterations at the first-line treatment failure of osimertinib. A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable. Moreover, the integration of FISH, NGS, and ddPCR provided a comprehensive assessment of MET amplification.

PMID: 41326340 [Indexed for MEDLINE]

33. Lancet Respir Med. 2025 Dec;13(12):1057-1066. doi: 10.1016/S2213-2600(25)00240-1. Epub 2025 Sep 28.

Durvalumab, carboplatin, and etoposide in patients who are treatment-naive with extensive-stage small-cell lung cancer and poor performance status (NEJ045A): a single-arm phase 2 trial.

BACKGROUND: Treating patients with extensive-stage small-cell lung cancer (SCLC) with poor performance status poses considerable challenges. We aimed to evaluate the combination of an immune checkpoint inhibitor with platinum-based therapy in this population.

METHODS: This open-label, single-arm phase 2 NEJ045A trial enrolled untreated patients with extensive-stage SCLC with performance status 2 or 3. Participants received four cycles of durvalumab, carboplatin, and etoposide, followed by durvalumab maintenance. A dose adjustment strategy was used, with initial reductions in carboplatin-etoposide dosages, subsequently adjusted based on adverse events, allowing for potential escalation. The primary endpoint was tolerability, assessed by the proportion of patients completing induction therapy. A key secondary endpoint was 1-year survival rate. This trial is registered at the Japan Registry of Clinical Trials (jRCTs031200319) and has been completed.

FINDINGS: Between April 8, 2021, and Oct 3, 2023, 57 patients (performance status 2 n=43 and performance status 3 n=14) were enrolled with a median age of 73·5 years (IQR 69·0-77·5), 44 (79%) of 56 were male. 26 (67%; 80% CI 55·2-76·7; p<0·0001) of 39 patients with performance status 2 and five (50%; 26·7-73·3; p=0·0088) of ten with performance status 3 completed induction therapy, exceeding the pre-specified threshold. Grade 3 or higher adverse events occurred in 52 (93%) of 56 patients, and 12 (21%) of 56 discontinued due to adverse events. The 1-year survival rates were 43·4% (80% CI 34·1-53·1) overall (p<0·0001), 50·0% (39·1-60·9) in performance status 2 (p<0·0001), and 18·2% (5·0-41·5) in performance status 3.

INTERPRETATION: Durvalumab, carboplatin, and etoposide showed tolerability and promising efficacy as a first-line treatment for patients with untreated extensive-stage SCLC with poor performance status, supporting the integration of immune checkpoint inhibitors in this therapeutically challenging population.

FUNDING: AstraZeneca KK.

PMID: 41033335 [Indexed for MEDLINE]

34. J Thorac Oncol. 2025 Dec;20(12):1814-1828. doi: 10.1016/j.jtho.2025.07.129. Epub 2025 Jul 30.

Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC.

INTRODUCTION: Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable responses in patients with previously treated HER2 (ERBB2) mutant (HER2m) metastatic NSCLC (mNSCLC) in the DESTINY-Lung02 primary analysis (December 23, 2022, data cutoff). This final analysis evaluated T-DXd efficacy and safety after 8 additional months of follow-up, including clinically relevant subgroups and patient-reported outcomes.

METHODS: DESTINY-Lung02 was a randomized, dose-blinded, multicenter, phase 2 trial. Patients with previously treated HER2m mNSCLC were randomized 2:1 to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. Primary end point was confirmed objective response rate by blinded independent central review.

RESULTS: As of August 25, 2023, 102 and 50 patients had received T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up (Q1-Q3) was 15.8 (8.2-20.7) months and 16.5 (9.4-20.8) months, respectively. Confirmed objective response rate (95% confidence interval) was 50.0% (51/102; 39.9%-60.1%) and 56.0% (28/50; 41.3%-70.0%), respectively. Safety profile was acceptable and generally manageable. Accordingly, median treatment duration (Q1-Q3) was 7.7 (3.7-14.4) months and 8.3 (2.8-13.1) months; drug-related grade 3 or higher treatment-emergent adverse events occurred in 39.6% (40/101) and 60.0% (30/50), with nausea most common (67.3% [68/101], 82.0% [41/50]). Adjudicated drug-related interstitial lung disease occurred in 14.9% (15/101) and 32.0% (16/50), mostly grade 1 or 2 with one grade 5 in each arm. Health-related quality of life was preserved for the duration of T-DXd treatment while sample size was sufficient for analysis, with no adverse effects on health-related quality of life observed at either dose.

CONCLUSIONS: T-DXd demonstrated strong and durable responses at both doses, with no clinically significant changes in toxicity. The approved 5.4-mg/kg dose demonstrated a more favorable benefit-risk profile, including lower adjudicated drug-related interstitial lung disease incidence.

GOV IDENTIFIER: NCT04644237.

PMID: 40749900 [Indexed for MEDLINE]

35. J Clin Oncol. 2025 Dec 10;43(35):3706-3713. doi: 10.1200/JCO-25-02023. Epub 2025 Oct 19.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

The phase II PHAROS study previously showed that encorafenib plus binimetinib has antitumor activity in patients with BRAF V600E-mutant metastatic non-small cell lung cancer (mNSCLC). In PHAROS, 98 patients (59 treatment-naïve; 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. We report updated results from data cutoff of March 14, 2025. The median duration of treatment with both encorafenib and binimetinib was 16.3 months in treatment-naïve and 5.5 months in previously treated patients. After median follow-up for overall survival (OS) of 52.3 months in treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not estimable); 4-year OS probability was 49% (95% CI, 35 to 62). After median follow-up for OS of 48.2 months in previously treated patients, mOS was 22.7 months (95% CI, 14.1 to 32.6); 4-year OS probability was 31% (95% CI, 16 to 47). In treatment-naïve and previously treated groups, 58% and 26% received ≥1 subsequent systemic anticancer treatment, respectively. Safety profile remained consistent with that in previous analyses. Although comparisons across trials should be done cautiously, to our knowledge, encorafenib plus binimetinib was associated with the longest mOS reported to date with targeted treatment in patients with treatment-naïve BRAF V600E-mutant mNSCLC.

PMID: 41109959 [Indexed for MEDLINE]

36. Sci Bull (Beijing). 2025 Dec 15;70(23):4046-4060. doi: 10.1016/j.scib.2025.10.024. Epub 2025 Oct 21.

LD-110, a potent LSD1 PROTAC degrader, suppresses tumor growth by inducing ER stress and apoptosis.

Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is frequently overexpressed in multiple cancer types and associated with poor prognosis of cancer patients. While LSD1 represents a compelling therapeutic target, clinical development of small-molecule inhibitors has been hampered by dose-limiting toxicities and off-target effects. In this study, we reported the discovery of LD-110 as a potent proteolysis targeting chimera (PROTAC) specifically engineered for LSD1 degradation. LD-110 effectively degrades LSD1 via the ubiquitin-proteasome system and significantly suppresses the growth and survival of breast and lung cancer cells. Mechanistically, LD-110 triggers endoplasmic reticulum stress by activating the ATF4-CHOP signal to increase NOXA levels, but decrease MCL1 levels, along with increasing ROS production and prolonged DNA damage to trigger phosphorylation of GCN2 and eIF2α for enhanced ATF4 translation, ultimately inducing apoptotic cell death. Importantly, LD-110 demonstrated a good in vivo pharmacokinetic profile and effectively inhibited in vivo tumor growth in breast and lung xenograft tumor models. Collectively, we discovered a potent PROTAC degrader targeting LSD1 with effective anti-cancer activity for future development as a promising anti-cancer agent.

PMID: 41188178 [Indexed for MEDLINE]