Immune checkpoint inhibitors have limited efficacy in SMARCA4-deficient non-small cell lung cancer

SMARCA4-deficient non-small cell lung cancer (SD-NSCLC) is a highly aggressive malignancy with a poor prognosis, and the clinical efficacy of immune checkpoint inhibitors (ICIs) in this context remains under investigation. This study focuses on patients with SD-NSCLC, investigating the efficacy of ICIs and the risk factors affecting prognosis, while also conducting a preliminary exploration of the underlying mechanisms through The Cancer Genome Atlas (TCGA) database.

From October 2020 to May 2025, 95 patients with SD-NSCLC, confirmed by immunohistochemistry (IHC) at Tianjin Medical University Cancer Institute & Hospital, were included for analysis. Validation and molecular mechanism exploration were conducted using the TCGA database. Disease-free survival (DFS) and progression-free survival (PFS) were the primary endpoints of the study. The disease control rate (DCR) was a secondary endpoint.

In stage IV SD-NSCLC patients, no significant difference in PFS was observed between those treated with ICIs and non-ICIs (P=0.60). However, the median PFS (mPFS) differences were significant between STK11/KEAP1 mutant-type (mut) and wild-type (wt) groups (1.0 vs. 6.5 months, P=0.007). Even after ICI treatment, the difference in mPFS between the STK11/KEAP1 wt and mut groups remained significant (P=0.02). Additionally, there was a significant difference in the mPFS between the SD group treated with ICIs and the non-SD group (6.0 vs. 11.0 months, P=0.003). TCGA analysis revealed that SMARCA4 loss-of-function (LOF) mutations had significantly shorter mPFS compared to non-LOF mutations (18.66 vs. 57.56 months, P=0.02). Differential gene expression and enrichment analysis, along with immune infiltration analysis, revealed that SMARCA4-LOF was associated with gene silencing and immune suppression, which may explain the limited efficacy of ICIs.

SMARCA4 deficiency is an independent prognostic factor for NSCLC, as validated using the TCGA database. Co-mutations with STK11/KEAP1 further exacerbate poor prognosis, suggesting that specific gene co-mutations may influence treatment response and survival. Moreover, SMARCA4 deficiency leads to poor responses to immunotherapy, potentially due to core metabolic disorders, inactivation of tumor suppressor signaling, and immune suppression in the tumor microenvironment. These findings suggest that treatment strategies should be adjusted to address these molecular mechanisms.