{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:42:47Z","timestamp":1791477767748,"version":"4.3.4"},"reference-count":110,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that has become central to prostate cancer (PCa) diagnostics and treatment. Beyond its enzymatic role in folate and glutamate metabolism, PSMA is upregulated in advanced PCa, where it contributes to angiogenesis, tumour progression, and therapeutic resistance. This review integrates current understanding of PSMA biology with an emphasis on the role of PSMA expression and the hallmarks of cancer-proliferative signalling, metabolic adaptation, and evasion of cell death. While PSMA has revolutionised theranostic strategies in PCa, its utility as a sole biomarker is limited in select cases such as neuroendocrine differentiation and discordant disease biology. To address these challenges, we highlight emerging biomarkers and novel imaging markers that complement PSMA, including genomic alterations, circulating tumour markers, and exosomal microRNAs. Advances in radiomics and dual-tracer positron emission tomography (PET) further refine patient selection by capturing aggressive low-PSMA phenotypes. Furthermore, PSMA-PET is showing promise in other malignancies, including renal cell carcinoma (RCC) and glioblastoma multiforme (GBM), where neovasculature expression may extend its theranostic applications beyond PCa. By situating PSMA within this broader biomarker landscape, we outline opportunities for theranostic integration, including predictive models, combination therapies and expansion into non-prostate malignancies. Understanding the biology of PSMA in conjunction with novel biomarkers provides a framework for optimising theranostic applications and advancing personalised cancer care.<\/jats:p>","DOI":"10.3390\/cancers17223717","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:02:42Z","timestamp":1763640162000},"page":"3717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["PSMA Theranostics in Prostate Cancer and Beyond: Current and Future Perspectives"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9659-2411","authenticated-orcid":false,"given":"Kieran","family":"Sandhu","sequence":"first","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"University of Cambridge, Cambridge CB2 1TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hennes","sequence":"additional","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan G.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-5618","authenticated-orcid":false,"given":"Nathan","family":"Lawrentschuk","sequence":"additional","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia"},{"name":"Department of Urology, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia"},{"name":"EJ Whitten Prostate Cancer Research Centre, Epworth Healthcare, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1138-6389","authenticated-orcid":false,"given":"Marlon","family":"Perera","sequence":"additional","affiliation":[{"name":"Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia"},{"name":"Department of Urology, Austin Hospital, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/S0140-6736(20)30314-7","article-title":"Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomised, multicentre study","volume":"395","author":"Hofman","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1056\/NEJMoa2107322","article-title":"Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer","volume":"385","author":"Sartor","year":"2021","journal-title":"N. 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