GRIN3A defines an immunosuppressive niche in advanced prostate cancer.

Early-stage prostate cancer is typically manageable with standard therapies, yet the eventual development of castration-resistant prostate cancer (CRPC) remains a significant barrier to effective clinical management. Specifically, the response to immunotherapy in CRPC remains limited, primarily due to a lack of predictive biomarkers and specific therapeutic targets. This study systematically integrates single-cell transcriptomic data across various disease stages, coupled with multi-dimensional validation, to reveal that glutamate ionotropic receptor NMDA type 3A (GRIN3A) expression is persistently elevated throughout tumor evolution and correlates significantly with advanced pathological stages and poor prognosis. Notably, during the transition to CRPC, tumor subpopulations with high GRIN3A expression exhibit pronounced immunoregulatory properties. Experimental validation demonstrated that GRIN3A levels inversely correlate with T-cell infiltration and promote an immunosuppressive microenvironment, partially mediated by TGF-β signaling activation. Furthermore, GRIN3A expression predicts the efficacy of immune checkpoint blockade (ICB) therapy and sensitivity to multiple chemotherapeutic agents. Collectively, these results suggest that GRIN3A has the potential to serve as a biomarker for tumor heterogeneity and immunotherapy resistance, providing a rationale for further exploration of strategies to overcome immune evasion in advanced PCa.