Addressing clinical needs in NSCLC immunotherapy: Mechanisms of resistance and promising combination strategies.

PD-(L)1 monoclonal antibody-based immunotherapy has become the cornerstone of treatment for non-small cell lung cancer without driver gene alterations. However, resistance, including primary and acquired resistance, remains a major clinical challenge. In this review, we summarize the delayed separation of progression-free survival curves observed in randomized clinical trials, which reflects the emergence of resistance at different treatment stages and the dynamic evolution of anti-tumor immune responses. The development of effective combination strategies should therefore be guided by a thorough understanding of the complex biological mechanisms governing tumor-immune interactions. We review the underlying mechanisms of immunotherapy resistance and propose potential combination strategies. Finally, we emphasize several key considerations for future clinical trial design, including the sequencing of combination therapies, biomarker-guided treatment selection, and optimized management of treatment-related toxicities.