Characteristics and therapeutic resistance mechanisms of the prostate cancer immune microenvironment: a comprehensive analysis from bench to clinic

The immunosuppressive, ‘cold’ tumor microenvironment (TME) of metastatic castration-resistant prostate cancer (mCRPC) is a primary cause of immunotherapy failure. This review delineates the androgen receptor (AR) signalling pathway as the central orchestrator of therapeutic resistance. AR activation directly suppresses CD8⁺ T-cell cytotoxicity, expands immunosuppressive myeloid and regulatory T-cell compartments, and drives spatial heterogeneity in immune infiltration. We highlight that responsive patient subsets can be identified by specific biomarkers—such as biallelic CDK12 inactivation or DNA damage repair deficiencies—which guide the use of immune checkpoint or PARP inhibitors. Emerging agents, including mutation-specific AR degraders and bispecific T-cell engagers, show potential to reprogramme the TME. However, clinical translation remains challenging, limited by discrepancies between preclinical models and human tumour ecology, coupled with dynamic evolution under therapeutic pressure. Overcoming resistance will require an integrated strategy combining high-resolution spatial multi-omics, advanced disease models, and biomarker-driven trials focused on rational combinations that co-target the AR pathway. Prioritizing this mechanistic approach is therefore critical to advance precision therapy for prostate cancer.