Targetable driver gene-tumor immune microenvironment axis in non-small cell lung cancer: from molecular pathological mechanisms to precision immunotherapy stratification strategies.

Non-small cell lung cancer (NSCLC) is characterized by substantial molecular heterogeneity that critically influences the efficacy of immunotherapy. Although immune checkpoint inhibitors (ICIs) have improved outcomes in selected patients, responses vary markedly across molecular subtypes defined by targetable driver gene alterations. Increasing evidence indicates that oncogenic drivers, including EGFR, ALK, KRAS, MET, RET, and BRAF, actively shape the tumor immune microenvironment (TIME) by regulating antigen presentation, immune cell infiltration, cytokine signaling, metabolic programs, and immune checkpoint expression. These interactions generate distinct driver gene-associated immune phenotypes that underlie differential sensitivity and resistance to ICIs. Recent advances in single-cell and spatial profiling have further revealed the complexity and spatial organization of these immune landscapes. In this review, we summarize current mechanistic and clinical evidence supporting the targetable driver gene-TIME axis in NSCLC and discuss its implications for immunotherapy response, resistance, and patient stratification. This integrative framework provides a rationale for precision immunotherapy strategies and the design of biomarker-driven clinical trials.