The landscape of targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC) has evolved significantly, particularly with the introduction of third-generation EGFR tyrosine kinase inhibitors (TKIs) like osimertinib and the novel ASK120067. Zhang et al. highlight that while these therapies show promising efficacy, acquired resistance remains a critical challenge, often linked to metabolic adaptations such as glycolytic activation (ref: Zhang doi.org/10.1038/s41392-024-01928-8/). In a multicenter phase III trial, Zhou et al. demonstrated that the combination of gefitinib with anlotinib significantly improved progression-free survival (PFS) in treatment-naïve patients, suggesting that dual inhibition of EGFR and vascular endothelial growth factor pathways can enhance therapeutic outcomes (ref: Zhou doi.org/10.1038/s41392-024-01927-9/). Conversely, Zhao et al. conducted a systematic review and meta-analysis, revealing that the efficacy of immune checkpoint inhibitors (ICIs) in patients who progressed on EGFR TKIs remains controversial, indicating a need for further exploration of ICI strategies in this refractory population (ref: Zhao doi.org/10.1016/S1470-2045(24)00379-6/). Furthermore, Yang et al. reported on the KEYNOTE-789 study, where the addition of pembrolizumab to chemotherapy did not significantly improve PFS compared to chemotherapy alone in TKI-resistant patients, raising questions about the role of ICIs in this context (ref: Yang doi.org/10.1200/JCO.23.02747/). Overall, while advancements in targeted therapies are promising, the emergence of resistance mechanisms necessitates ongoing research into combination strategies and novel agents.

Immunotherapy has emerged as a pivotal component in the treatment of advanced non-small cell lung cancer (NSCLC), particularly in combination with traditional chemotherapy. Shiraishi et al. conducted a phase III trial comparing platinum-based chemotherapy with pembrolizumab versus a combination of chemotherapy with nivolumab and ipilimumab, revealing that the addition of a CTLA-4 inhibitor did not yield a significant survival benefit, highlighting the complexity of immune modulation in NSCLC treatment (ref: Shiraishi doi.org/10.1016/S2213-2600(24)00185-1/). Zhao et al.'s systematic review and meta-analysis further elucidated the role of ICIs in patients with advanced EGFR-mutated NSCLC who have progressed on TKIs, indicating that while ICIs may offer some benefits, their overall efficacy remains uncertain in this challenging cohort (ref: Zhao doi.org/10.1016/S1470-2045(24)00379-6/). Additionally, the study by Rekhtman et al. on chromothripsis-mediated SCLC provides insights into the genomic underpinnings of aggressive lung cancers, suggesting that understanding these mechanisms may inform future immunotherapeutic strategies (ref: Rekhtman doi.org/10.1158/2159-8290.CD-24-0286/). Collectively, these studies underscore the need for tailored immunotherapeutic approaches that consider individual tumor biology and prior treatment history.

Radiotherapy remains a cornerstone in the treatment of lung cancer, particularly in stage III NSCLC, where its integration with immunotherapy and chemotherapy is being actively explored. Vera et al. conducted a randomized phase 2 trial assessing adaptive radiotherapy with doses up to 74 Gy, demonstrating that this approach could enhance treatment efficacy while maintaining safety in patients without EGFR mutations (ref: Vera doi.org/10.1016/S1470-2045(24)00320-6/). In a different context, Ni et al. reported on the SWORD trial, which evaluated the combination of sintilimab, stereotactic body radiotherapy (SBRT), and granulocyte-macrophage colony-stimulating factor in metastatic NSCLC, achieving a notable objective response rate of 36.7%, thereby supporting the potential of combining immunotherapy with localized radiotherapy (ref: Ni doi.org/10.1038/s41467-024-51807-7/). Furthermore, He et al. performed a meta-analysis comparing proton therapy to photon therapy for early-stage NSCLC, concluding that while proton therapy shows promise, more robust evidence is needed to establish its superiority over conventional methods (ref: He doi.org/10.1186/s40364-024-00642-5/). These findings collectively highlight the evolving role of radiotherapy in lung cancer management, particularly when combined with novel therapeutic agents.

The metabolic reprogramming of cancer cells is increasingly recognized as a critical factor in tumor progression and resistance to therapy. Wu et al. investigated the role of 6-phosphogluconate dehydrogenase (PGD) in lung adenocarcinoma, finding that its inhibition led to reduced glycolysis and fatty acid synthesis, thereby mitigating tumor cell proliferation and invasion (ref: Wu doi.org/10.1016/j.canlet.2024.217177/). Similarly, Zhou et al. highlighted the importance of histone methyltransferase NSD3, which inhibits glycolysis through interaction with PPP1CB, suggesting that its downregulation correlates with poor survival outcomes in lung adenocarcinoma (ref: Zhou doi.org/10.1002/advs.202400381/). Additionally, Zhang et al. reported elevated levels of histone lactylation in NSCLC tissues, which were associated with immune evasion and poor prognosis, indicating that epigenetic modifications may play a significant role in tumor microenvironment dynamics (ref: Zhang doi.org/10.1158/0008-5472.CAN-23-3513/). These studies collectively underscore the intricate relationship between metabolic pathways and cancer progression, suggesting that targeting metabolic vulnerabilities may offer new therapeutic avenues.

The identification of biomarkers and prognostic factors is essential for improving treatment outcomes in lung cancer. Rekhtman et al. focused on chromothripsis in small cell lung carcinoma (SCLC), revealing that this genomic phenomenon is associated with aggressive tumor behavior and may serve as a prognostic marker for treatment response (ref: Rekhtman doi.org/10.1158/2159-8290.CD-24-0286/). Their findings suggest that chromothripsis could be a valuable indicator of tumor biology, particularly in patients who are non-smokers or light smokers, thereby challenging traditional risk profiles associated with SCLC. The integration of such biomarkers into clinical practice could enhance personalized treatment strategies, allowing for more tailored therapeutic approaches based on individual tumor characteristics.

Understanding the molecular mechanisms underlying resistance to therapy is crucial for developing effective treatment strategies in lung cancer. Zhao et al. conducted a systematic review and meta-analysis that highlighted the challenges of using immune checkpoint inhibitors (ICIs) in patients with advanced EGFR-mutated NSCLC who have progressed on TKIs, indicating that resistance mechanisms may limit the effectiveness of these therapies (ref: Zhao doi.org/10.1016/S1470-2045(24)00379-6/). This underscores the need for further research into the molecular pathways involved in resistance, particularly in the context of combination therapies. Additionally, the studies on metabolic alterations in lung cancer, such as those by Wu and Zhou, suggest that targeting metabolic pathways may provide a novel approach to overcoming resistance and improving patient outcomes (ref: Wu doi.org/10.1016/j.canlet.2024.217177/; ref: Zhou doi.org/10.1002/advs.202400381/). Collectively, these insights into molecular mechanisms and resistance highlight the complexity of lung cancer treatment and the necessity for ongoing research to identify effective strategies.

Clinical trials play a pivotal role in advancing treatment strategies for lung cancer, particularly in the context of targeted therapies and immunotherapy. Zhou et al. conducted a phase III trial demonstrating that the combination of gefitinib and anlotinib significantly improved progression-free survival in treatment-naïve patients with EGFR-mutated advanced NSCLC, suggesting a promising dual-target approach (ref: Zhou doi.org/10.1038/s41392-024-01927-9/). In contrast, Zhao et al.'s systematic review on ICIs in patients who progressed on EGFR TKIs revealed mixed results regarding their efficacy, indicating that while some patients may benefit, the overall effectiveness remains uncertain (ref: Zhao doi.org/10.1016/S1470-2045(24)00379-6/). These findings emphasize the importance of ongoing clinical research to refine treatment protocols and identify optimal combinations that can enhance patient outcomes in lung cancer management.

Emerging therapies and novel approaches are critical in addressing the challenges of resistance in lung cancer treatment. Zhang et al. explored the role of branched-chain amino acid transaminase 1 in conferring resistance to EGFR TKIs through epigenetic glycolytic activation, highlighting a potential target for overcoming resistance mechanisms (ref: Zhang doi.org/10.1038/s41392-024-01928-8/). This study underscores the need for innovative strategies that can effectively counteract resistance pathways. Additionally, the integration of novel agents with existing therapies, as seen in the combination of gefitinib and anlotinib, demonstrates the potential for enhanced efficacy in treating EGFR-mutated NSCLC (ref: Zhou doi.org/10.1038/s41392-024-01927-9/). As research continues to unveil new therapeutic targets and combinations, the landscape of lung cancer treatment is poised for significant advancements.