Prostate cancer remains a substantial health challenge, with >375,000 annual deaths amongst men worldwide. Most prostate cancer-related deaths are attributable to the development of resistance to standard-of-care treatments. Characterization of the diverse and complex surfaceome of treatment-resistant prostate cancer, combined with advances in drug development that leverage cell-surface proteins to enhance drug delivery or activate the immune system, have provided novel therapeutic opportunities to target advanced prostate cancer. The prostate cancer surfaceome, including proteins such as prostate-specific membrane antigen (PSMA), B7-H3, six transmembrane epithelial antigen of the prostate 1 (STEAP1), delta-like ligand 3 (DLL3), trophoblastic cell-surface antigen 2 (TROP2), prostate stem cell antigen (PSCA), HER3, CD46 and CD36, can be exploited as therapeutic targets, as regulatory mechanisms might contribute to the heterogeneity of expression of these proteins and subsequently affect treatment response and resistance. Specific treatment strategies targeting the surfaceome are in clinical development, including radionuclides, antibody-drug conjugates, T cell engagers and chimeric antigen receptor (CAR) T cells. Ultimately, biomarker development and clinical implementation of these agents will be informed and refined by further understanding of the biology of various targets; the target specificity and sensitivity of different agents; and off-target and toxic effects associated with these agents. Understanding the dynamic nature of cell-surface targets and non-overlapping expression patterns might also lead to future combinational strategies.
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