{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T17:00:07Z","timestamp":1772730007405,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Prostate cancer frequently progresses to lethal, drug-resistant castration-resistant prostate cancer (CRPC), where conventional therapies often fail due to intrinsic and acquired resistance mechanisms. This resistance creates a critical therapeutic impasse, leaving patients with limited options and poor prognoses. Immunotherapy has emerged as a promising strategy to harness the immune system against these treatment-refractory tumors, offering a potential avenue to overcome the immunosuppressive barriers that underlie CRPC drug resistance. This review synthesizes findings from a structured search of PubMed, Web of Science, and Embase (2020\u20132025), revealing significant clinical progress: 4 vaccine trials, 5 immune checkpoint inhibitor trials, 18 combination therapy trials (\u22652 agents), and 6 targeted drug trials have been conducted. Preliminary efficacy was observed in novel approaches like bispecific antibodies (e.g., Xaluritamig achieving 59% PSA50 response), PSMA-CAR-T (P-PSMA-101), and oncolytic viruses (Ad5 PSA\/MUC-1\/brachyury). Basic research identified four targeted resistance mechanisms (e.g., AR-LLT1, Pygo2, and HnRNP L) and one nanoparticle-mediated triple-combination therapy (CM-AMS@AD NPs integrating photothermal, chemotherapy, and immunotherapy), which enhanced cytotoxic T-cell infiltration and suppressed CRPC growth preclinically. These collective findings suggest the potential of immunotherapy for CRPC in overcoming resistance barriers and improving patient outcomes, with bispecific T cell engagers (Xaluritamig, 59% PSA50) and PSMA-directed CAR-T therapy (P-PSMA-101, &gt;50% PSA reduction) emerging as the most promising near-term candidates and biomarker-stratified combinations (nivolumab plus rucaparib, 84.6% PSA50, in HRR-deficient patients) illustrating the transformative power of precision patient selection; however, these findings require validation in larger, biomarker-stratified trials before definitive conclusions can be drawn. Translating this potential into clinical reality requires optimized patient selection through predictive biomarkers and rigorously validated Phase III trials to confirm durable clinical responses and long-term survival benefits.<\/jats:p>","DOI":"10.3390\/cimb48030282","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T15:29:53Z","timestamp":1772724593000},"page":"282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Immunotherapeutic Strategies for Castration-Resistant Prostate Cancer: Mechanisms and Clinical Advances"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4658-0823","authenticated-orcid":false,"given":"Xuantao","family":"Xia","sequence":"first","affiliation":[{"name":"Faculty of Chinese Medicine, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwei","family":"Xia","sequence":"additional","affiliation":[{"name":"Guangxi Innovation Center of Zhuang Yao Medicine, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4625-3957","authenticated-orcid":false,"given":"Lili","family":"Yu","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macao 999078, China"},{"name":"Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute, Zhuhai 519099, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0090-4295(99)00471-9","article-title":"Clinical states in prostate cancer: Toward a dynamic model of disease progression","volume":"55","author":"Scher","year":"2000","journal-title":"Urology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1200\/JCO.2016.72.1068","article-title":"Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA","volume":"35","author":"Oudard","year":"2017","journal-title":"J. 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