GRIN3A defines an immunosuppressive niche in advanced prostate cancer

Prostate cancer (PCa) is a highly heterogeneous malignancy characterized by complex progression. In particular, upon progression to castration-resistant prostate cancer (CRPC), the response to immunotherapy is limited, which is primarily attributable to the lack of specific immunotherapeutic targets and biomarkers capable of accurately predicting treatment efficacy. Through systematic integration of single-cell transcriptomic data across multiple disease stages, this study revealed that glutamate ionotropic receptor NMDA type 3A (GRIN3A) expression is not only persistently elevated throughout tumor evolution but also significantly correlates with advanced pathological stages and adverse prognoses. Notably, during the transition to CRPC, tumor cell subpopulations with high GRIN3A expression exhibit pronounced immunoregulatory properties. Experimental validation has demonstrated that GRIN3A expression levels inversely correlate with T-cell infiltration and promote the formation of an immunosuppressive microenvironment, which is mediated in part through activation of the TGF-β signaling pathway. Furthermore, GRIN3A expression is predictive of the efficacy of immune checkpoint blockade (ICB) therapy and sensitivity to multiple chemotherapeutic agents. Collectively, GRIN3A functions as a dual biomarker indicative of both tumor heterogeneity evolution and immunotherapy resistance. These findings provide a novel theoretical basis for overcoming immune evasion in advanced prostate cancer and advancing precision therapeutic strategies.​