{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:58:38Z","timestamp":1785337118144,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"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. Oncol."],"abstract":"<jats:p>Prostate cancer (PCa) remains a leading cause of cancer-related death in men, characterized by a notoriously immunosuppressive tumor microenvironment (TME) that renders it largely refractory to immune checkpoint inhibitors (ICIs). This \u201ccold\u201d tumor phenotype is orchestrated by a complex network of molecular mechanisms, rather than a simple absence of antigens. Here, we provide a focused review of the key molecular drivers enforcing immune evasion in PCa, moving beyond cellular descriptions to the underlying genomic and signaling aberrations. We dissect the roles of tumor-intrinsic oncogenic pathways, specifically the androgen receptor (AR) signaling axis, PTEN\/PI3K\/AKT activation, and loss of tumor suppressors like TP53 and RB1, in sculpting an immunosuppressive secretome. Furthermore, we explore the paradoxical role of genomic instability, where defects in mismatch repair (dMMR) and homologous recombination deficiency (HRD) create neoantigens but simultaneously foster immune exclusion through the cyclic GMP-AMP synthase\/stimulator of interferon genes (cGAS\/STING) pathway and immunosuppressive cytokines. We discuss emerging controversies, including the immunostimulatory versus immunosuppressive duality of AR signaling and the role of the STING pathway in promoting a pro-metastatic inflammatory state. Critically, we highlight that many of these mechanistic insights are predominantly derived from preclinical models, and their direct translation to clinical responses remains an ongoing challenge. The field is also constrained by a lack of robust, validated predictive biomarkers beyond dMMR. Moreover, the mechanisms of immune evasion in treatment-emergent neuroendocrine prostate cancer (NEPC) represent a critical knowledge gap, hindering immunotherapy development for this aggressive variant. Future therapeutic strategies must pivot from a monotherapy paradigm to rationally designed molecular combinations that leverage our deepening understanding of these intricate mechanisms to convert the TME from an immune desert into an inflamed, ICI-responsive hub.<\/jats:p>","DOI":"10.3389\/fonc.2026.1882249","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:59:55Z","timestamp":1785333595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The molecular underpinnings of the immune landscape in prostate cancer: decoding a \u201ccold\u201d tumor"],"prefix":"10.3389","volume":"16","author":[{"given":"Kaili","family":"Li","sequence":"first","affiliation":[{"name":"Urological Surgical Department, Wenshang County People\u2019s Hospital","place":["Jining, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Urological Surgical Department, Wenshang County People\u2019s Hospital","place":["Jining, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denghui","family":"Huang","sequence":"additional","affiliation":[{"name":"Urological Surgical Department, Wenshang County People\u2019s Hospital","place":["Jining, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70189-5","article-title":"Ipilimumab versus placebo 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