Background <p>In this study, we aimed to identify oncofetal antigens expressed in prostate cancer and systematically examine their potential role using theranostic approaches. Cell surface oncofetal antigens are expressed to a limited extent in adult cells and may be variably expressed in tumor cells. The fact that oncofetal proteins are not expressed in healthy cells minimizes the risk of systemic toxicity, especially when using targeted therapies. Cell surface oncofetal proteins identified in prostate cancer are CEACAM5, Trop-2 (TACSTD2), Glypican-3 (GPC3), ROR1 (NTRKR1), and 5T4 (TPBG).</p> Main body <p>In accordance with PRISMA guidelines, we conducted a systematic review of peer-reviewed articles indexed in Scopus, PubMed and Web of Science databases until February 10, 2025. Studies evaluating the expression, biological role, and therapeutic relevance of cell surface oncofetal antigens in PC were included. Data extraction focused on their functional role in prostate cancer, associated radiopharmaceuticals, and clinical or preclinical therapeutic strategies. Five key oncofetal proteins: CEACAM5, Trop-2, ROR1, GPC3, and 5T4 have been consistently identified in the literature. These proteins have been associated with aggressive PC subtypes, including neuroendocrine and castration-resistant forms; and are linked to key signaling pathways such as Wnt/β-Catenin, EMT, and PI3K/AKT. Several investigational agents targeting these antigens, including antibody-drug conjugates (ADCs), CAR-T cells and radiolabeled imaging probes (e.g. ⁶⁸Ga, ⁸⁹Zr, ⁶⁴Cu, ²²⁵Ac) are being developed and evaluated in both preclinical and early clinical settings.</p> Conclusion <p>CEACAM5, Trop-2, 5T4, GPC3, and ROR1 oncofetal proteins are variably expressed in advanced prostate cancer. Therapeutics and radiopharmaceutical imaging agents targeting these proteins are in development. Though provocative findings are apparent, considerable clinical research is needed to determine the value of targeting these proteins.</p>