Immunotherapy has emerged as a pivotal treatment for advanced non-small-cell lung cancer (NSCLC), particularly through immune checkpoint blockade (ICB) strategies. A study by Skoulidis demonstrated that dual blockade with CTLA4 and PD-(L)1 inhibitors significantly enhances anti-tumor activity compared to PD-(L)1 inhibitors alone, although the absence of validated biomarkers complicates patient selection (ref: Skoulidis doi.org/10.1038/s41586-024-07943-7/). Fu's research further elucidated the mechanisms of resistance in lung cancer brain metastasis, revealing that tyrosine kinase inhibitor (TKI) treatment elevates CTLA4 expression in T cells, fostering an immune-suppressive microenvironment (ref: Fu doi.org/10.1016/j.ccell.2024.09.012/). Alban's investigation into neoantigen immunogenicity found that early loss of mutations during nivolumab treatment correlates with clinical benefit, suggesting that neoantigen dynamics are crucial for treatment efficacy (ref: Alban doi.org/10.1038/s41591-024-03240-y/). Huang's study identified proliferating Treg cells as potential predictors of immunotherapy benefit, emphasizing the need for dynamic immune profiling in clinical trials (ref: Huang doi.org/10.1038/s41392-024-01988-w/). Additionally, the TD-NeoFOUR trial by Duan assessed the safety and efficacy of neoadjuvant sintilimab combined with anlotinib and chemotherapy, indicating promising outcomes for resectable NSCLC (ref: Duan doi.org/10.1038/s41392-024-01992-0/). Li's work on small cell transformation in EGFR-mutant lung adenocarcinomas highlighted the molecular characteristics associated with this resistance mechanism, which complicates treatment strategies (ref: Li doi.org/10.1038/s41392-024-01981-3/). Provencio's analysis of neoadjuvant chemotherapy and nivolumab revealed significant treatment-related adverse events, underscoring the need for careful patient monitoring (ref: Provencio doi.org/10.1016/S1470-2045(24)00498-4/). Lastly, Aokage's trial on neoadjuvant pembrolizumab and ramucirumab demonstrated its influence on the tumor microenvironment, further supporting the integration of immunotherapy in treatment regimens (ref: Aokage doi.org/10.1158/1078-0432.CCR-24-1561/).

The landscape of genomic alterations in lung cancer is rapidly evolving, particularly concerning actionable mutations and their implications for targeted therapies. Tang's study established a link between obesity and specific driver mutations in lung adenocarcinoma, suggesting that obesity may influence tumor genotype independently of other factors (ref: Tang doi.org/10.1038/s41588-024-01969-3/). Puttick's research on HLA disruption revealed significant variability in HLA allelic expression, which is critical for understanding immune evasion in cancer evolution (ref: Puttick doi.org/10.1038/s41588-024-01883-8/). Dall'Olio's analysis of metabolic tumor volume (MTV) as a predictive biomarker for immune checkpoint blockers highlighted that high MTV correlates with poor overall survival, driven by systemic inflammation and genomic instability (ref: Dall'Olio doi.org/10.1158/1078-0432.CCR-24-1993/). Hong's extensive study on ERBB2 alterations in NSCLC patients identified actionable mutations that can guide targeted therapy decisions, emphasizing the need for comprehensive genomic profiling (ref: Hong doi.org/10.1038/s41698-024-00720-9/). Meng's investigation into lymph node metastasis in lung adenocarcinoma provided insights into the immunogenomic patterns associated with metastatic progression, which could inform treatment strategies (ref: Meng doi.org/10.1186/s40164-024-00574-8/). Zhu's work on CD73's role in NSCLC metastasis revealed its regulatory influence on epithelial-to-mesenchymal transition, highlighting potential therapeutic targets (ref: Zhu doi.org/10.1073/pnas.2404709121/). Saalfeld's study on small cell transformation in EGFR-mutated NSCLC further elucidated the efficacy of immune checkpoint inhibitors and TKIs in combination with chemotherapy, providing critical data on treatment outcomes (ref: Saalfeld doi.org/10.1016/j.ejca.2024.115065/).

The tumor microenvironment (TME) plays a crucial role in modulating responses to therapy in NSCLC, particularly in the context of immunotherapy. Lee's comprehensive metabolomic analysis identified key biomarkers related to amino acid and glycolysis metabolism that could predict immunotherapy response, suggesting that metabolic modulation may enhance treatment efficacy (ref: Lee doi.org/10.1016/j.drup.2024.101159/). Jaeger-Ruckstuhl's phase I study on ROR1-specific CAR-T cells demonstrated promising antitumor responses in hematopoietic and epithelial malignancies, indicating the potential of CAR-T cell therapy in targeting specific tumor microenvironments (ref: Jaeger-Ruckstuhl doi.org/10.1158/1078-0432.CCR-24-2172/). Huang's investigation into Ku70's nonclassical functions revealed its role in Treg-suppressive function, which may influence immune responses within the TME (ref: Huang doi.org/10.1172/JCI178079/). Dall'Olio's findings on metabolic tumor volume as a predictive biomarker for immune checkpoint blockers further emphasize the interplay between metabolism and immune response in NSCLC (ref: Dall'Olio doi.org/10.1158/1078-0432.CCR-24-1993/). Wang's deep learning analysis of histopathological images provided a novel prognostic signature for predicting immunotherapy outcomes, highlighting the importance of TME features in treatment response (ref: Wang doi.org/10.1038/s41416-024-02856-8/). Boscolo Bragadin's longitudinal liquid biopsy study identified molecular variables associated with clinical benefit from immunotherapy, reinforcing the relevance of dynamic monitoring of the TME (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/). Zheng's research on neural infiltration-mediated metabolic reprogramming illustrated the complex interactions between neural elements and tumor progression, suggesting new avenues for therapeutic intervention (ref: Zheng doi.org/10.1186/s13046-024-03202-9/).

Clinical outcomes in NSCLC are increasingly influenced by genomic alterations and immune landscape, with emerging biomarkers providing insights into treatment efficacy. Wang's research identified LTBR as a novel immune checkpoint in tumor-associated macrophages, highlighting its potential as a target for overcoming ICI resistance (ref: Wang doi.org/10.1002/imt2.233/). Zhou's study on actionable genomic alterations revealed their significant impact on the efficacy of neoadjuvant immunotherapy, emphasizing the need for personalized treatment approaches based on genomic profiling (ref: Zhou doi.org/10.1136/jitc-2024-009677/). Marinelli's systematic review and meta-analysis demonstrated that achieving a major pathologic response significantly improves event-free survival in patients treated with neoadjuvant chemoimmunotherapy, regardless of adjuvant treatment (ref: Marinelli doi.org/10.1016/j.jtho.2024.09.1443/). Nie's multicenter cohort study explored the controversial association between obesity and survival outcomes in advanced NSCLC, finding that obesity may improve overall survival in male patients treated with chemotherapy (ref: Nie doi.org/10.1186/s12916-024-03688-2/). Han's updated analysis from the LASER201 study provided critical insights into overall survival in patients with EGFR T790M-positive advanced NSCLC treated with lazertinib, reinforcing the importance of targeted therapies (ref: Han doi.org/10.1186/s12916-024-03620-8/). Sun's investigation into respiratory sarcopenia as a postoperative risk stratification tool highlighted its significance in predicting complications and survival outcomes (ref: Sun doi.org/10.1001/jamasurg.2024.4800/). Li's multiregional transcriptomic profiling study underscored the prognostic value of regional gene expression in localized NSCLC, suggesting that tailored approaches may enhance predictive accuracy (ref: Li doi.org/10.1038/s41698-024-00680-0/).

Surgical and radiotherapy approaches in NSCLC are evolving, with recent studies emphasizing the integration of these modalities with systemic therapies. Sun's phase III trial demonstrated that thoracic radiotherapy significantly improves survival in patients with oligo-organ metastatic NSCLC, highlighting the potential of combining radiotherapy with targeted therapies (ref: Sun doi.org/10.1200/JCO.23.02075/). Lee's metabolomic analysis identified biomarkers that could enhance the efficacy of immunotherapy, suggesting that understanding metabolic pathways may inform surgical decisions (ref: Lee doi.org/10.1016/j.drup.2024.101159/). Trestini's observational study on body composition derangements in lung cancer patients receiving pembrolizumab revealed that pre-treatment body composition may influence treatment outcomes, indicating a need for personalized surgical strategies (ref: Trestini doi.org/10.1002/jcsm.13568/). Aokage's trial on neoadjuvant pembrolizumab and ramucirumab provided insights into the effects of these therapies on the tumor microenvironment, which could inform surgical timing and approaches (ref: Aokage doi.org/10.1158/1078-0432.CCR-24-1561/). Vanstraelen's study on decision-making processes for stereotactic body radiotherapy versus minimally invasive surgery highlighted the complexities involved in selecting appropriate treatment modalities for early-stage NSCLC (ref: Vanstraelen doi.org/10.1097/SLA.0000000000006552/).

Body composition and cachexia are critical factors influencing treatment outcomes in lung cancer patients. Nie's multicenter cohort study found that obesity is associated with improved overall survival in advanced NSCLC patients treated with chemotherapy, suggesting that body mass index may serve as a prognostic factor (ref: Nie doi.org/10.1186/s12916-024-03688-2/). Miura's research on cachexia in advanced NSCLC patients indicated that approximately one-third of patients experience this condition, which complicates treatment and affects chemotherapy efficacy (ref: Miura doi.org/10.1002/jcsm.13606/). Trestini's study on body composition phenotypes in patients receiving pembrolizumab revealed that these phenotypes may reflect immunological responses and influence clinical outcomes, emphasizing the need for tailored treatment strategies (ref: Trestini doi.org/10.1002/jcsm.13568/). Zheng's investigation into neural infiltration-mediated metabolic reprogramming highlighted the interplay between neural elements and tumor progression, suggesting that understanding these interactions could inform cachexia management (ref: Zheng doi.org/10.1186/s13046-024-03202-9/). Boscolo Bragadin's longitudinal liquid biopsy study underscored the importance of monitoring molecular changes in relation to body composition and treatment response in advanced NSCLC (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/).

Neural infiltration is increasingly recognized as a significant factor in tumor progression and treatment response in NSCLC. Zheng's study on neural infiltration-mediated tumor metabolic reprogramming revealed that infiltrating nerves can stimulate tumor growth and dissemination, suggesting that neural elements play a critical role in the tumor microenvironment (ref: Zheng doi.org/10.1186/s13046-024-03202-9/). Boscolo Bragadin's longitudinal liquid biopsy research highlighted the heterogeneity of clinical benefit from immunotherapy, emphasizing the need to consider neural interactions in treatment planning (ref: Boscolo Bragadin doi.org/10.1038/s41698-024-00704-9/). Zhou's phase 3 EVEREST trial on zorifertinib demonstrated its efficacy in patients with CNS metastases, reinforcing the importance of targeting neural pathways in treatment strategies (ref: Zhou doi.org/10.1016/j.medj.2024.09.002/). The interplay between neural elements and tumor cells suggests that therapeutic approaches addressing neural infiltration may enhance treatment outcomes and provide new avenues for intervention.

Emerging biomarkers and therapeutic targets are reshaping the landscape of NSCLC treatment, particularly in the context of immunotherapy and targeted therapies. Huang's research on Ku70 revealed its nonclassical role in promoting Treg-suppressive function, suggesting that it may serve as a novel target for enhancing antitumor immunity (ref: Huang doi.org/10.1172/JCI178079/). Dall'Olio's study on metabolic tumor volume (MTV) as a predictive biomarker for immune checkpoint blockers highlighted the correlation between high MTV and poor overall survival, indicating that metabolic profiling could guide treatment decisions (ref: Dall'Olio doi.org/10.1158/1078-0432.CCR-24-1993/). Aokage's trial on neoadjuvant pembrolizumab and ramucirumab provided insights into the tumor microenvironment's influence on treatment outcomes, emphasizing the need for biomarkers that reflect TME dynamics (ref: Aokage doi.org/10.1158/1078-0432.CCR-24-1561/). These studies collectively underscore the importance of integrating emerging biomarkers into clinical practice to optimize treatment strategies and improve patient outcomes.