Recent studies have highlighted the complexities of resistance mechanisms in lung cancer, particularly in the context of immunotherapy. Skoulidis et al. demonstrated that CTLA4 blockade can effectively overcome KEAP1/STK11-related resistance to PD-(L)1 inhibitors in advanced non-small-cell lung cancer (NSCLC), suggesting that dual immune checkpoint blockade may enhance anti-tumor activity compared to PD-(L)1 inhibitors alone (ref: Skoulidis doi.org/10.1038/s41586-024-07943-7/). Fu et al. further explored the role of CTLA4 in lung cancer brain metastasis, revealing that TKI treatment elevates CTLA4 expression in T cells, which contributes to an immune-suppressive microenvironment, complicating treatment outcomes (ref: Fu doi.org/10.1016/j.ccell.2024.09.012/). Alban et al. investigated neoantigen immunogenicity in patients undergoing nivolumab therapy, finding that early loss of mutations and neoantigens correlates with clinical benefit, emphasizing the importance of tumor evolution during treatment (ref: Alban doi.org/10.1038/s41591-024-03240-y/). Additionally, Li et al. examined the transformation of EGFR-mutant lung adenocarcinomas into small cell lung cancer (SCLC), identifying transcriptomic characteristics that may inform treatment strategies (ref: Li doi.org/10.1038/s41392-024-01981-3/). These findings collectively underscore the need for personalized approaches in immunotherapy, considering the dynamic nature of tumor biology and resistance mechanisms.

The landscape of targeted therapies for NSCLC continues to evolve, with several recent studies providing insights into novel combinations and molecular alterations. Shi et al. reported promising results from the ALTER-L038 study, where the combination of benmelstobart and anlotinib demonstrated anti-tumor efficacy in EGFR-positive advanced NSCLC patients who had previously failed EGFR TKI therapy (ref: Shi doi.org/10.1038/s41392-024-01982-2/). Wolf et al. presented final results from the GEOMETRY mono-1 trial, confirming the efficacy of capmatinib in patients with MET exon 14 mutations, reinforcing its role as a viable treatment option (ref: Wolf doi.org/10.1016/S1470-2045(24)00441-8/). The NADIM trial highlighted the effectiveness of perioperative chemotherapy combined with nivolumab, showing significant clinical outcomes in resectable NSCLC (ref: Provencio doi.org/10.1016/S1470-2045(24)00498-4/). Hochmair et al. evaluated pembrolizumab with or without maintenance olaparib, finding no significant overall survival benefit but suggesting potential for improved progression-free survival (ref: Hochmair doi.org/10.1016/j.jtho.2024.10.012/). These studies illustrate the ongoing refinement of targeted therapies and the importance of understanding molecular alterations to optimize treatment strategies in NSCLC.

Clinical trials remain pivotal in shaping treatment paradigms for NSCLC, with recent studies providing critical insights into therapeutic efficacy and safety. The TD-NeoFOUR trial evaluated neoadjuvant sintilimab combined with anlotinib and chemotherapy, demonstrating promising efficacy and safety profiles in resectable NSCLC (ref: Duan doi.org/10.1038/s41392-024-01992-0/). Sun et al. conducted a phase III trial that revealed thoracic radiotherapy significantly improves survival in patients with oligo-organ metastatic NSCLC, emphasizing the role of radiotherapy in comprehensive treatment plans (ref: Sun doi.org/10.1200/JCO.23.02075/). The RAMOSE trial compared osimertinib with and without ramucirumab, showing that dual inhibition may delay resistance emergence, although results are still pending (ref: Le doi.org/10.1200/JCO.24.00533/). Furthermore, the RATIONALE-307 and RATIONALE-304 trials provided insights into the combination of tislelizumab with chemotherapy, demonstrating improved progression-free survival and manageable safety profiles (ref: Wang doi.org/10.1016/j.esmoop.2024.103727/; ref: Lu doi.org/10.1016/j.esmoop.2024.103728/). These findings collectively highlight the importance of ongoing clinical research in optimizing treatment outcomes for NSCLC patients.

The identification of biomarkers and predictive factors is crucial for enhancing treatment efficacy in lung cancer. Wang et al. introduced LTBR as a novel immune checkpoint in tumor-associated macrophages, suggesting its potential as a target to overcome immune checkpoint inhibitor resistance (ref: Wang doi.org/10.1002/imt2.233/). Boscolo Bragadin et al. conducted a longitudinal liquid biopsy study, revealing that cfDNA dynamics can predict clinical benefit from immunotherapy in advanced NSCLC, highlighting the utility of liquid biopsies in monitoring treatment response (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/). Farris et al. performed a secondary analysis of CALGB 30610-RTOG 0538, identifying significant prognostic factors in limited-stage small cell lung cancer, emphasizing the impact of nodal involvement on overall survival (ref: Farris doi.org/10.1001/jamanetworkopen.2024.40673/). Shen et al. explored the role of MAT1A in NSCLC progression, linking its activation of glycolysis to tumor advancement (ref: Shen doi.org/10.1038/s41419-024-07113-7/). These studies underscore the critical role of biomarkers in personalizing treatment strategies and improving patient outcomes in lung cancer.

Small cell lung cancer (SCLC) presents unique challenges in treatment, as evidenced by recent studies exploring novel therapeutic strategies. Meador et al. reported on a phase I/II trial combining olaparib and temozolomide, demonstrating potential efficacy in recurrent SCLC, particularly in terms of central nervous system outcomes (ref: Meador doi.org/10.1158/1078-0432.CCR-24-2350/). Dall'Olio et al. highlighted the prognostic significance of metabolic tumor volume in advanced NSCLC, suggesting that high tMTV correlates with poorer survival outcomes, which may also apply to SCLC (ref: Dall'Olio doi.org/10.1158/1078-0432.CCR-24-1993/). Additionally, Montégut et al. discussed the role of DBI/ACBP in enhancing anticancer immunosurveillance, linking metabolic factors to cancer progression (ref: Montégut doi.org/10.1080/15548627.2024.2411854/). These findings reflect the ongoing need to address the complexities of SCLC treatment and the importance of integrating novel therapeutic approaches.

Understanding the mechanisms of metastasis and the tumor microenvironment is critical in lung cancer research. Zhu et al. identified that CD73 promotes NSCLC metastasis through Axl signaling, which regulates epithelial-to-mesenchymal transition (EMT), highlighting a potential therapeutic target (ref: Zhu doi.org/10.1073/pnas.2404709121/). Boscolo Bragadin et al. further emphasized the role of liquid biopsies in predicting clinical outcomes, demonstrating that molecular changes can inform treatment efficacy (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/). Li et al. conducted multiregional transcriptomic profiling, revealing that regional gene expression patterns can provide improved prognostic insights in localized NSCLC, suggesting that tumor heterogeneity plays a significant role in treatment outcomes (ref: Li doi.org/10.1038/s41698-024-00680-0/). Huang et al. explored the combined inhibition of MET and VEGF pathways, showing that this approach can enhance the sensitivity of EGFR TKIs in resistant NSCLC models (ref: Huang doi.org/10.1186/s40164-024-00565-9/). These studies collectively underscore the intricate interplay between metastasis, the tumor microenvironment, and therapeutic responses in lung cancer.

Radiotherapy continues to play a vital role in the treatment of lung cancer, particularly when combined with systemic therapies. Sun et al. demonstrated that thoracic radiotherapy significantly improves survival in patients with oligo-organ metastatic NSCLC, reinforcing the importance of integrating radiotherapy into treatment regimens (ref: Sun doi.org/10.1200/JCO.23.02075/). Provencio et al. reported on the NADIM trial, which evaluated the combination of perioperative chemotherapy and nivolumab, showing promising clinical outcomes and manageable adverse events (ref: Provencio doi.org/10.1016/S1470-2045(24)00498-4/). Hochmair et al. assessed the efficacy of pembrolizumab with or without maintenance olaparib, finding that while overall survival did not significantly differ, progression-free survival was improved in the combination group (ref: Hochmair doi.org/10.1016/j.jtho.2024.10.012/). These findings highlight the potential of combined modalities in enhancing treatment efficacy and patient outcomes in lung cancer.

Emerging therapeutic strategies and novel agents are reshaping the landscape of lung cancer treatment. Lee et al. conducted a comprehensive metabolomic analysis, identifying key biomarkers that modulate immunotherapy response in NSCLC patients, suggesting that metabolic pathways could be targeted to enhance treatment efficacy (ref: Lee doi.org/10.1016/j.drup.2024.101159/). Wang et al. introduced LTBR as a novel immune checkpoint in tumor-associated macrophages, indicating its potential as a target to overcome resistance to immune checkpoint inhibitors (ref: Wang doi.org/10.1002/imt2.233/). Boscolo Bragadin et al. further explored the predictive power of longitudinal liquid biopsies in assessing clinical benefit from immunotherapy, emphasizing the importance of real-time monitoring of treatment response (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/). Zhou et al. presented the first-in-human study of IBI351, a potent irreversible inhibitor of KRAS G12C, showing promising results in patients with advanced solid tumors, including NSCLC (ref: Zhou doi.org/10.1016/j.ejca.2024.114337/). These studies reflect the ongoing innovation in lung cancer therapies, highlighting the importance of integrating novel agents and strategies into clinical practice.