Abstract: SMARCA4 serves as the core ATPase subunit of the SWI/SNF chromatin remodeling complex. Its functional loss occurs in approximately 5–10% of non-small cell lung cancer (NSCLC) cases and is closely associated with aggressive phenotypes, chemotherapy resistance, and primary resistance to immunotherapy. This review systematically summarizes the molecular characteristics induced by SMARCA4 deficiency, including transcriptional dysregulation, DNA repair defects, and immunosuppressive microenvironment, with a particular focus on the resulting "synthetic lethal" vulnerabilities. Accumulating evidence suggests that ATR inhibitors, EZH2 inhibitors, and CDK4/6 inhibitors can selectively kill SMARCA4-deficient tumor cells under specific contexts, particularly exhibiting synergistic potential when combined with immune checkpoint inhibitors. Based on current clinical data, we propose an optimized diagnostic and therapeutic pathway for SMARCA4-deficient NSCLC: routine molecular testing, prioritized enrollment in targeted-immunotherapy combination trials, and avoidance of immunotherapy monotherapy misuse. This review aims to provide mechanism-guided novel therapeutic strategies and clinical practice references for this refractory subtype.