Clinical outcomes and immune contexture in SMARCA4-deficient gastric cancer patients.

Exploiting vulnerabilities in switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes for cancer therapy is a promising therapeutic strategy. The SWI/SNF chromatin remodeling complex acts as a regulatory component of transcription, and our previous study found an immune-active microenvironment and better response to immunotherapy of gastric cancer with ARID1A loss. However, little is known about the clinical significance of SMARCA4, which encodes for another subunit of the SWI/SNF complex, in gastric cancer (GC) patients. This study analyzed the association of SMARCA4 status with clinicopathological features, survival outcomes, therapeutic response, and immune microenvironment characteristics in three independent cohorts: Zhongshan Hospital (ZSHS) cohort (n = 442), Zhongshan Hospital immune checkpoint blockade (ZSHS-ICB) cohort (n = 41), and Samsung Medical Center cohort (SMC, n = 51). SMARCA4-deficient GC patients exhibit clinicopathological features associated with enhanced tumor aggressiveness, including a higher prevalence of poorly differentiated disease (p = 0.034), pN3 stage at diagnosis (p = 0.059), E-cadherin negative expression (p < 0.001), and genomically stable (GS) and microsatellite stable/epithelial-mesenchymal transition molecular subtype (MSS/EMT) (p < 0.001 and p < 0.001, respectively). Kaplan-Meier analysis revealed that SMARCA4 deficiency indicated poor prognosis in GC (p < 0.001). Moreover, SMARCA4 deficiency identified a subgroup of GC patients who exhibited poor outcomes despite receiving adjuvant chemotherapy in the GS subtype (p = 0.029). In contrast, these patients demonstrated increased sensitivity to anti-PD-1 therapy in both the ZSHS-ICB (p = 0.039) and SMC (p = 0.062) cohorts. Immunological analysis revealed a distinct immune profile characterized by abundant but exhausted CD8 T cells in SMARCA4-deficient GC. In conclusion, patients with SMARCA4-deficient GC patients demonstrated poor prognosis but improved response to immunotherapy. These observed clinical outcomes may be attributed to the immunosuppressive microenvironment, highlighting the potential for developing novel therapeutic approaches. © 2025 The Pathological Society of Great Britain and Ireland.