Tumor‑immune spatiotemporal co‑evolution: A new paradigm for understanding and overcoming therapy resistance in metastatic castration‑resistant prostate cancer (Review).

Metastatic castration‑resistant prostate cancer (mCRPC) remains an incurable disease characterized by relentless progression and universal resistance to standard therapies. The limited efficacy of immunotherapies in this malignancy reflects an immunosuppressive tumor microenvironment orchestrated by regulatory T cells, myeloid‑derived suppressor cells, tumor‑associated macrophages and cancer‑associated fibroblasts, along with androgen receptor signaling, metabolic reprogramming and spatially organized immune exclusion zones. The present review synthesized emerging evidence from single‑cell and spatial transcriptomics to propose a spatiotemporal coevolution paradigm, wherein resistance emerges not through linear genetic selection alone but through dynamic, reciprocal interactions among tumor cells, stromal components and immune populations across both temporal and spatial dimensions. The framework integrates clonal evolution dynamics, preexisting castration‑tolerant progenitors, fibroblast‑dominated barriers and metabolic crosstalk that collectively enforce immune evasion. Key therapeutic vulnerabilities, including YAP1‑TGF‑β1 axis disruption, PKMYT1 inhibition, metabolic targeting and biomarker‑guided patient stratification, are critically evaluated within this ecological context. Ultimately, the present review aimed to establish spatiotemporal co‑evolution as a unifying framework that transforms mCRPC from a uniformly fatal disease into a chronically manageable condition through precisely timed, spatially informed and mechanistically rational interventions.