Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a poor prognosis, characterized by early dissemination and a five-year overall survival rate of less than 7%. Recent multiomics analyses of 314 SCLCs revealed significant insights into the tumor's intrinsic and extrinsic signatures, highlighting the role of ASCL1 in therapeutic vulnerability (ref: Wang doi.org/10.1038/s41392-025-02378-6/). In a phase 1b study, the combination of tarlatamab with PD-L1 inhibitors, such as atezolizumab or durvalumab, was evaluated as first-line maintenance therapy following chemo-immunotherapy in extensive-stage SCLC. The study included 88 patients and reported a median time of 3.76 months from the start of first-line therapy to the initiation of tarlatamab maintenance (ref: Paulson doi.org/10.1016/S1470-2045(25)00480-2/). Additionally, the phase Ib study of GSK3326595, a PRMT5 inhibitor, demonstrated its potential as a monotherapy and in combination with pembrolizumab, indicating a promising avenue for advanced cancers, including SCLC (ref: Gounder doi.org/10.1016/j.annonc.2025.08.3757/).

The interplay between DNA methylation and genomic alterations is crucial in the evolution of non-small cell lung cancer (NSCLC). A study utilizing reduced representation bisulfite sequencing on 217 tumor samples identified significant aberrations in DNA methylation, providing insights into tumor evolution and potential biomarkers for patient stratification (ref: Gimeno-Valiente doi.org/10.1038/s41588-025-02307-x/). The International Association for the Study of Lung Cancer's staging project revealed that patients with EGFR-mutated tumors had significantly better overall survival across all TNM stages, while those with KRAS mutations exhibited worse outcomes, emphasizing the importance of molecular alterations in prognosis (ref: Carbone doi.org/10.1016/j.jtho.2025.06.025/). Furthermore, smoking status was found to negatively impact lung cancer staging and overall survival, suggesting that integrating smoking history into staging could enhance prognostic accuracy (ref: Eng doi.org/10.1016/j.jtho.2025.07.002/).

Recent studies have highlighted the benefits of combining immune checkpoint inhibitors (ICIs) with radiotherapy in NSCLC, particularly for patients with brain metastases. A retrospective analysis showed improved survival for patients receiving concurrent ICI and radiotherapy compared to those receiving sequential treatment (ref: Liu doi.org/10.5306/wjco.v16.i8.107009/). Additionally, the inhibition of autophagy was found to enhance the efficacy of anlotinib and PD-1 inhibitors, suggesting that targeting the tumor microenvironment could improve immunotherapy outcomes (ref: Tang doi.org/10.1136/jitc-2024-010812/). However, the presence of clonal hematopoiesis was associated with reduced responses to atezolizumab, indicating that this genetic alteration may serve as a predictive biomarker for ICI treatment in NSCLC (ref: Chat doi.org/10.1136/jitc-2025-011565/).

Understanding the cellular origins of cancers through single-cell chromatin landscapes has become pivotal in identifying tumor development mechanisms. A comprehensive analysis involving 3,669 whole genome sequencing samples and 559 single-cell chromatin profiles successfully predicted the cellular origins of 37 cancer subtypes, enhancing diagnostic and therapeutic strategies (ref: Bairakdar doi.org/10.1038/s41467-025-63957-3/). In NSCLC, the study of EGFR exon 20 insertions revealed differential responses to various tyrosine kinase inhibitors (TKIs), with near-loop insertions showing greater sensitivity compared to far-loop insertions (ref: Le doi.org/10.1038/s41467-025-61817-8/). Additionally, the identification of nicotinamide N-methyltransferase (NNMT) as a driver of metabolic reprogramming in TKI-resistant cells presents a new therapeutic vulnerability and potential biomarkers for resistance (ref: Pulido doi.org/10.1016/j.canlet.2025.218032/).

The impact of smoking status on lung cancer staging and overall survival was evaluated in a large cohort, revealing that smokers had poorer prognoses compared to non-smokers, emphasizing the need for tailored management strategies (ref: Eng doi.org/10.1016/j.jtho.2025.07.002/). Furthermore, the International Association for the Study of Lung Cancer's analysis indicated that patients with EGFR mutations had significantly improved overall survival across all stages, while those with KRAS mutations faced worse outcomes, highlighting the importance of molecular profiling in clinical decision-making (ref: Carbone doi.org/10.1016/j.jtho.2025.06.025/). The COCOON trial demonstrated that enhanced dermatologic management with amivantamab-lazertinib improved quality of life and reduced dermatologic adverse events, showcasing the importance of supportive care in managing treatment-related side effects (ref: Cho doi.org/10.1016/j.jtho.2025.07.117/).

Innovative therapeutic strategies are being explored to combat resistance in lung cancer. The identification of NNMT-driven metabolic reprogramming in TKI-resistant NSCLC cells has revealed a potential druggable vulnerability, suggesting that targeting this pathway could enhance treatment efficacy (ref: Pulido doi.org/10.1016/j.canlet.2025.218032/). The phase Ib study of GSK3326595, a PRMT5 inhibitor, demonstrated promising results as both a monotherapy and in combination with pembrolizumab, indicating its potential role in advanced cancers (ref: Gounder doi.org/10.1016/j.annonc.2025.08.3757/). Additionally, the exploration of TWF2 as a mediator of tumor progression and resistance in renal cell carcinoma underscores the need for further investigation into molecular mechanisms that drive therapeutic resistance (ref: Fu doi.org/10.1002/advs.202506367/).

The integration of radiotherapy with immunotherapy has shown promising results in enhancing treatment efficacy for NSCLC. A study evaluating the effects of concurrent immune checkpoint inhibitors and radiotherapy in patients with brain metastases demonstrated improved survival outcomes, suggesting that this combination could be a viable treatment strategy (ref: Liu doi.org/10.5306/wjco.v16.i8.107009/). Furthermore, the development of a ferroptosis-oriented radiosensitization strategy aims to overcome radioresistance in NSCLC, highlighting the potential of targeting specific pathways to enhance the effectiveness of radiotherapy (ref: Aishajiang doi.org/10.1016/j.biomaterials.2025.123675/). The phase Ib study of GSK3326595 also indicates the potential for combining targeted therapies with immunotherapy to improve clinical outcomes in advanced cancers (ref: Gounder doi.org/10.1016/j.annonc.2025.08.3757/).