An integrated analysis of SLC7A11 as a pan-cancer immunotherapeutic biomarker with experimental validation of its regulation by miR-148b-3p in breast cancer

Background Identifying reliable biomarkers for immunotherapy response remains challenging. Solute carrier family 7 member 11 (SLC7A11), a key regulator of redox homeostasis and ferroptosis, demonstrates significant tumor-promoting potential across cancers, yet its pan-cancer associations with immunotherapy-related features and interaction with microRNAs in triple-negative breast cancer pathogenesis remain elusive. Methods We systematically analyzed SLC7A11 expression across cancer types using TCGA and GTEx data, and evaluated its associations with immunotherapy-related features. Survival analyses were assessed in general and immunotherapy-treated cohorts. A miRNA regulatory network targeting SLC7A11 was constructed in breast cancer and the SLC7A11-miR-148b-3p axis was tested via in vitro experiments in triple-negative breast cancer (TNBC) cell models (MDA-MB-231 and MDA-MB-468). Results Pan-cancer analysis revealed upregulation of SLC7A11 transcriptional expression in over 88% tumor types, and associations with established immunotherapy-related features, including tumor mutational burden, microsatellite instability, PD-L1 expression, and immune infiltration. Higher SLC7A11 expression was associated with improved response to immunotherapy, but inferior prognosis in most tumors, including breast cancer. In TNBC cell models, in vitro experiments supported that miR-148b-3p negatively regulated SLC7A11, and higher SLC7A11 expression was associated with increased glutathione levels, reduced lipid peroxidation, and enhanced cell survival under ferroptosis-inducing conditions. Conclusions Our pan-cancer analyses reveal a potential biological link between SLC7A11, ferroptosis, and tumor immunity, generating the hypothesis that SLC7A11 may serve as a biomarker for immune checkpoint inhibitor response. In TNBC models, we identify the miR-148b-3p/SLC7A11 axis as a potential regulator of ferroptosis resistance based on in vitro findings, warranting further in vivo validation.