SMARCA4-deficient non-small cell lung cancer and immunotherapy resistance: mechanisms and novel strategies—a mini-review

SMARCA4 deficient thoracic tumors represent an aggressive subset of malignancies characterized by inactivating mutations in the SMARCA4 gene, a core component of the SWI/SNF chromatin remodeling complex. These tumors, including SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) and SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT), typically occur in older male smokers. They are characterized by poor differentiation, advanced stage at diagnosis, and a dismal prognosis. Despite the transformative impact of immune checkpoint inhibitors (ICIs) in advanced NSCLC, patients with SMARCA4-deficient tumors often demonstrate limited responses due to an immunosuppressive tumor microenvironment (TME), characterized by minimal T-cell infiltration, impaired antigen presentation, and epigenetic dysregulation. Co-mutations in STK11 and KEAP1 further contribute to immune evasion and resistance to immunotherapy. While conventional biomarkers such as PD-L1 expression and tumor mutational burden (TMB) show limited predictive value in this context, preliminary evidence from retrospective studies and case series suggests that specific mutation classes and combinatorial therapeutic approaches—such as chemoimmunotherapy, anti-angiogenic agents, and ferroptosis inducers—may enhance clinical outcomes. This review synthesizes current knowledge on the clinicopathological and molecular features of SMARCA4-dNSCLC, explores mechanisms of immunotherapy resistance, and evaluates therapeutic strategies. Where instructive, insights from the related SMARCA4-UT are integrated to provide a comparative perspective on the profound impact of SMARCA4 deficiency across thoracic malignancies.