Spatial and single-cell insights into the prostate cancer microenvironment: overcoming immunotherapy resistance through multidimensional strategies

Abstract

Despite breakthroughs in immune checkpoint inhibitors (ICIs) across various malignancies, prostate cancer (PCa), particularly metastatic castration-resistant prostate cancer (mCRPC), has shown limited responses to ICIs. This pervasive primary resistance is fundamentally driven by the canonically “immune-cold” and highly immunosuppressive tumor microenvironment (TME) of PCa. Propelled by recent advancements in single-cell RNA sequencing and spatial transcriptomics, this review comprehensively deconstructs the dynamic spatiotemporal evolution of the PCa immune landscape across localized, mCRPC, and lineage-plastic variant stages (e.g., neuroendocrine and double-negative PCa). We systematically delineate how the profound immune-excluded phenotype is sculpted not by isolated events, but by an intricate, multicellular suppressive ecosystem. Specifically, we detail the subclonal heterogeneity, spatial topography, and metabolic crosstalk of key suppressive populations, including specific tumor-associated macrophage (TAM) subsets, regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs). Furthermore, we elucidate the tumor-intrinsic genetic aberrations (e.g., PTEN inactivation, TP53 mutations) and epigenetic rewiring (e.g., EZH2, CHD1, ARID1A dysregulation) that initiate and perpetually orchestrate this suppressive network. Finally, we highlight emerging therapeutic vulnerabilities and future translational directions. Dismantling the microenvironmental barriers in PCa necessitates transcending singular ICI blockade by employing novel combinatorial strategies that target chemotactic recruitment axes (e.g., CXCR2/CXCR4), reverse metabolic plasticity, and abrogate epigenetic silencing. Coupled with high-resolution liquid biopsy biomarkers (e.g., ctDNA, B7-H3+ EVs) for precise patient stratification and cutting-edge synthetic biology interventions, these multidimensional approaches hold profound promise for reversing the dual metabolic and immune suppressive state of PCa, thereby overcoming clinical immunotherapy resistance.