Prostate-Specific Membrane Antigen-Targeted Phototherapy for Prostate Cancer: A Systematic Review of Preclinical Evidence and Translational Readiness

Prostate-specific membrane antigen (PSMA) is an established diagnostic and therapeutic target in prostate cancer. PSMA-targeted phototherapy comprises mechanistically distinct full-antibody near-infrared photoimmunotherapy (NIR-PIT), antibody-fragment photoimmunotherapy, ligand-targeted photodynamic therapy (PDT), and nanoparticle or multimodal systems. This systematic review evaluated their preclinical efficacy, safety, and translational readiness. MEDLINE/PubMed, Embase, Scopus, Web of Science Core Collection, the Cochrane Library, and ClinicalTrials.gov were searched for studies published from 1 January 2010 to 20 August 2026. Studies were classified into four carrier–mechanism groups before comparison across a seven-domain translational-readiness framework with explicit Early, Developing and Advanced anchors. Owing to substantial heterogeneity in targeting platforms, photoactive agents, models, illumination parameters and outcomes, meta-analysis was inappropriate; synthesis followed SWiM guidance. Animal studies were assessed using SYRCLE, and in vitro or ex vivo studies using an adapted ToxRTool with a decision-relevant reporting overlay. No numerical result used in the synthesis was obtained by figure digitisation. Thirty-three studies were included: 10 were confined to in vitro experiments, 19 combined in vitro and in vivo work, and four were in vivo only; one of the 19 combined studies also assessed fresh human prostate tissue ex vivo. Platforms were analysed as full-antibody NIR-PIT or photoimmunotherapy, antibody-fragment photoimmunotherapy, ligand-targeted PDT, and nanoparticle or multimodal systems. Within these classes, reports generally demonstrated preferential PSMA-dependent uptake and light-induced cytotoxicity, with multiple murine studies reporting tumour-growth inhibition and longer time to humane endpoints. Durable tumour-free responses occurred in selected small cohorts, particularly after repeated or combination treatment. Translational evidence remained limited: one study evaluated orthotopic prostate treatment in four dogs, while another demonstrated treatment-induced apoptosis in fresh prostate cancer tissue from 17 prostatectomy patients. No included full report described therapeutic treatment in patients. The decision-relevant in vitro/ex vivo appraisal classified 17 reports as higher, eight as moderate and four as lower reliability; animal studies frequently lacked sufficient reporting of randomisation, allocation concealment and blinding. Major translational barriers were heterogeneous PSMA expression, non-standardised light delivery, limited long-term safety data and insufficient validation in anatomically and immunologically representative models. PSMA-targeted phototherapy shows preclinical activity but remains clinically immature. Translation should proceed within mechanistically defined therapeutic classes and prioritise clinically realistic light dosimetry, PSMA heterogeneity, pharmacokinetic optimisation, functional safety, independent validation, and staged human evaluation. PROSPERO registration number CRD420261483194.