{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:38:46Z","timestamp":1790699926953,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    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\u20132b) from speculative hypotheses (Level 3\u20134), 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\n                    <jats:italic>\u201cDynamic Monitoring\u2014Mechanistic Parsing\u2014Synergistic Intervention\u201d<\/jats:italic>\n                    framework, with concrete, clinically actionable strategies grounded in 2024\u20132025 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.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1797299","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T06:53:26Z","timestamp":1773212006000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Tumor-immune spatiotemporal co-evolution as a paradigm for overcoming therapy resistance in advanced prostate cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Junchao","family":"Xue","sequence":"first","affiliation":[{"name":"Tongde Hospital of Zhejiang Province","place":["Hangzhou, 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