The landscape of immunotherapy in lung cancer, particularly non-small cell lung cancer (NSCLC), has been significantly shaped by immune checkpoint inhibitors (ICIs) such as PD-1 and PD-L1 blockers. A study by Han et al. explored the predictive value of nuclear AhR and membranous PD-L1 expression in NSCLC patients undergoing PD-1 blockade, revealing that these biomarkers could effectively predict treatment responses (ref: Han doi.org/10.1038/s41392-023-01416-5/). El Zarif et al. provided insights into the safety and efficacy of ICIs in people living with HIV, demonstrating comparable outcomes between HIV-positive and HIV-negative patients with metastatic NSCLC, thus challenging previous assumptions about the exclusion of HIV patients from clinical trials (ref: El Zarif doi.org/10.1200/JCO.22.02459/). Furthermore, Zhao et al. reported promising results from a phase I/Ib trial of QL1706, a bifunctional PD1/CTLA4 dual blocker, which showed an overall response rate of 24.2% in NSCLC patients, indicating potential for enhanced therapeutic strategies (ref: Zhao doi.org/10.1186/s13045-023-01445-1/). However, van Gulijk et al. highlighted that PD-L1 blockade can promote regulatory T cell activity, contributing to therapy resistance, thus emphasizing the complexity of immune responses in cancer treatment (ref: van Gulijk doi.org/10.1126/sciimmunol.abn6173/). The FDA's approval of nivolumab combined with platinum-doublet chemotherapy for neoadjuvant treatment of resectable NSCLC further underscores the evolving treatment paradigms in this field (ref: Akinboro doi.org/10.1200/JCO.22.02509/).

Targeted therapies in NSCLC have shown promise, yet resistance mechanisms remain a significant challenge. A randomized trial by Shepherd et al. demonstrated that docetaxel could extend survival compared to best supportive care in patients previously treated with platinum-based chemotherapy, underscoring the need for effective second-line treatments (ref: Shepherd doi.org/10.1200/JCO.22.02545/). In another pivotal study, Hanna et al. compared pemetrexed to docetaxel, revealing that while both treatments are viable options, patient selection based on individual characteristics is crucial for optimizing outcomes (ref: Hanna doi.org/10.1200/JCO.22.02546/). Lim et al. introduced BBT-176, a novel fourth-generation tyrosine kinase inhibitor, which showed significantly lower IC50 values against osimertinib-resistant EGFR mutations, suggesting a potential solution to resistance (ref: Lim doi.org/10.1158/1078-0432.CCR-22-3901/). Zhang et al. discussed the necessity of combinatorial approaches to overcome PD-1/PD-(L)1 pathway resistance, emphasizing the urgent need for innovative trial designs to enhance treatment efficacy (ref: Zhang doi.org/10.1136/jitc-2022-006555/). Notably, Reck et al. reported improved systemic and intracranial outcomes with nivolumab plus ipilimumab in patients with baseline brain metastases, reinforcing the efficacy of combination therapies in challenging patient populations (ref: Reck doi.org/10.1016/j.jtho.2023.04.021/).

The genomic landscape of lung cancer is complex, with ongoing research aimed at elucidating the molecular underpinnings of the disease. Ely et al. developed a prime editor mouse model that allows for the modeling of a broad spectrum of somatic mutations, providing a powerful tool for studying lung cancer genetics (ref: Ely doi.org/10.1038/s41587-023-01783-y/). Zhou et al. identified that SYK-mediated epithelial cell states influence responses to c-Met inhibitors, suggesting that understanding cellular plasticity could enhance treatment stratification for NSCLC patients (ref: Zhou doi.org/10.1038/s41392-023-01403-w/). In a study focused on large-cell lung carcinoma, Guo et al. found recurrent mutations in the PI3K pathway, which were associated with more aggressive tumor phenotypes, highlighting the need for targeted therapies against these mutations (ref: Guo doi.org/10.1038/s41416-023-02301-2/). Borm et al. explored the predictive value of early response evaluation using FDG-PET-CT and T cell profiling, emphasizing the importance of biomarkers in assessing treatment efficacy in NSCLC (ref: Borm doi.org/10.1080/2162402X.2023.2204745/). Furthermore, Aggarwal et al. demonstrated that high tumor mutational burden correlates with improved outcomes in patients treated with immunotherapy, reinforcing the role of genomic profiling in personalized medicine (ref: Aggarwal doi.org/10.1001/jamanetworkopen.2023.11181/).

Clinical trials remain the cornerstone of advancing treatment options for lung cancer, with recent studies providing critical insights into therapeutic efficacy and safety. Akinboro et al. detailed the FDA's approval of nivolumab combined with platinum-doublet chemotherapy for neoadjuvant treatment of resectable NSCLC, based on the results of the CheckMate 816 trial, which demonstrated significant improvements in surgical outcomes (ref: Akinboro doi.org/10.1200/JCO.22.02509/). El Zarif et al. reported on the safety and activity of ICIs in people living with HIV, finding that treatment outcomes were comparable to those in HIV-negative populations, thus expanding the applicability of ICIs (ref: El Zarif doi.org/10.1200/JCO.22.02459/). In a phase I/Ib study, Zhao et al. found that QL1706, a bifunctional PD1/CTLA4 dual blocker, showed promising antitumor activity in advanced solid tumors, particularly NSCLC, with an overall response rate of 24.2% (ref: Zhao doi.org/10.1186/s13045-023-01445-1/). The comparative efficacy of docetaxel versus pemetrexed was evaluated by Hanna et al., revealing that both agents are effective in previously treated NSCLC, but patient selection remains critical for optimizing outcomes (ref: Hanna doi.org/10.1200/JCO.22.02546/). Additionally, Reck et al. highlighted the superior outcomes of nivolumab plus ipilimumab in patients with baseline brain metastases, further supporting the efficacy of combination therapies in this challenging cohort (ref: Reck doi.org/10.1016/j.jtho.2023.04.021/).

The tumor microenvironment plays a pivotal role in lung cancer progression and treatment response, with recent studies shedding light on immune infiltration patterns. Parra et al. characterized the spatial distribution of immune cells in NSCLC, identifying distinct cellular patterns associated with patient outcomes, where unmixed patterns correlated with immunoprotective cells while mixed patterns were linked to immunosuppressive cells (ref: Parra doi.org/10.1038/s41467-023-37905-y/). Cheng et al. found that immune infiltration in both tumor and adjacent non-neoplastic regions significantly influenced clinical outcomes in early-stage lung cancer, suggesting that comprehensive immune profiling could enhance prognostic assessments (ref: Cheng doi.org/10.1016/j.jtho.2023.04.022/). Sandström Gerdtsson et al. examined the phenotypic characteristics of tumor-infiltrating leukocytes, revealing that these cells exhibited higher levels of immune suppressive markers compared to stromal leukocytes, which could inform therapeutic strategies targeting the immune microenvironment (ref: Sandström Gerdtsson doi.org/10.1080/2162402X.2023.2206725/). Furthermore, Berko et al. utilized circulating tumor DNA to track resistance mechanisms in ALK-driven neuroblastoma, emphasizing the importance of monitoring tumor evolution in response to targeted therapies (ref: Berko doi.org/10.1038/s41467-023-38195-0/).

Socioeconomic factors significantly influence treatment access and outcomes in lung cancer, with recent studies highlighting persistent disparities. Norris et al. conducted a population-based cohort study revealing marked socioeconomic inequalities in the utilization of novel NSCLC treatments, even within a publicly funded healthcare system, indicating that access to advanced therapies is not equitably distributed (ref: Norris doi.org/10.1016/j.jtho.2023.04.018/). Cheng et al. further explored the relationship between immune infiltration and clinical outcomes, finding that higher immune infiltration in adjacent non-neoplastic regions correlated with better prognostic outcomes, suggesting that socioeconomic factors may also influence immune landscape and treatment efficacy (ref: Cheng doi.org/10.1016/j.jtho.2023.04.022/). Garon et al. reported on the safety and antitumor activity of durvalumab plus tremelimumab in patients previously treated with PD-(L)1 inhibitors, highlighting the need for equitable access to combination therapies that may benefit underrepresented populations (ref: Garon doi.org/10.1016/j.jtho.2023.04.020/). The findings from Reck et al. on improved outcomes with nivolumab plus ipilimumab in patients with brain metastases further underscore the necessity of addressing disparities in treatment access and outcomes across diverse patient populations (ref: Reck doi.org/10.1016/j.jtho.2023.04.021/).

The identification of reliable biomarkers is crucial for optimizing treatment strategies in lung cancer, particularly in the context of immunotherapy. Ghiringhelli et al. introduced the Immunoscore-Immune-Checkpoint (Immunoscore-IC), a novel diagnostic test that quantifies CD8 and PD-L1 markers, demonstrating its predictive value for the efficacy of anti-PD-1/PD-L1 therapies in NSCLC (ref: Ghiringhelli doi.org/10.1016/j.ebiom.2023.104633/). Attig et al. explored the role of human endogenous retrovirus (HERV) transcription in lung squamous cell carcinoma, finding that elevated HERVH levels correlated with improved survival, thus presenting a potential biomarker for patient stratification (ref: Attig doi.org/10.1172/JCI164397/). Sandström Gerdtsson et al. characterized immune infiltration niches in NSCLC, revealing that tumor-infiltrating leukocytes exhibited higher levels of immune suppressive markers, which could serve as predictive indicators for treatment response (ref: Sandström Gerdtsson doi.org/10.1080/2162402X.2023.2206725/). Lee et al. emphasized the need for continued exploration of KRAS G12C inhibitors and their pharmacodynamic profiling to address resistance mechanisms, reinforcing the importance of biomarker-driven approaches in lung cancer therapy (ref: Lee doi.org/10.1158/1535-7163.MCT-22-0810/). Additionally, Chour et al. reported on the increased risk of hepatotoxicity associated with sequential anti-PD-(L)1 and sotorasib therapy, highlighting the need for careful monitoring of adverse events in biomarker-driven treatment strategies (ref: Chour doi.org/10.1016/j.jtho.2023.05.013/).