Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) is orchestrated not only by tumor-intrinsic genomic alterations but also by dynamic reprogramming of the tumor microenvironment (TME). This review introduces the tumor-immune spatiotemporal co-evolution paradigm, which reframes mCRPC resistance as an ecosystem-level adaptation unfolding across temporal (disease stage) and spatial (niche architecture) dimensions. We synthesize clinical and multi-omics data to map a probabilistic evolutionary trajectory from an immune-permissive state, through suppressive niche consolidation, to a terminal immune desert phenotype. In this review, we systematically apply the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 criteria to this field, grading all mechanistic claims to explicitly distinguish peer-reviewed, validated findings (Level 1–2b) from speculative hypotheses (Level 3–4), and delineate 5 evidence-graded core conclusions of the tumor-immune co-evolution paradigm. We delineate how spatially organized cancer-associated fibroblast (CAF) subsets architect immunosuppressive niches and engage in reciprocal metabolic symbiosis with tumor cells, and redefine therapeutics as dominant selective pressures that drive clonal-stromal co-selection to explain cross-resistance across treatment modalities. To translate this paradigm, we propose an integrative closed-loop “Dynamic Monitoring—Mechanistic Parsing—Synergistic Intervention” framework, with concrete, clinically actionable strategies grounded in 2024–2025 peer-reviewed prostate cancer research. This framework advocates for longitudinal ecological auditing of the TME to rationally guide mechanistically orthogonal combination therapies. Our objective is to provide a rigorously evidence-based roadmap for transforming mCRPC into a chronically manageable condition through precision ecological intervention, offering a novel, actionable perspective to advance prostate cancer immunotherapy and overcome immune evasion for researchers and clinicians in the field of cancer immunology.
Xue et al. (2026) studied this question.