Photodynamic therapy remodels cutaneous tumor immunity: innate priming, suppressive feedback, and translational...

Photodynamic therapy (PDT) is an established local treatment for actinic keratoses, Bowen disease, and selected low-risk basal cell carcinomas, but its potential to reshape antitumor immunity may extend its value beyond direct phototoxicity. We conducted a narrative synthesis of clinical, translational, and mechanistic evidence, supplemented by targeted searches through August 2026, and appraised major findings using a three-level evidence-maturity framework. Current evidence supports a temporally organized model in which PDT-induced reactive oxygen species promote tumor and microvascular injury, immunogenic cell death, damage-associated molecular pattern release, tumor-antigen exposure, innate immune-cell recruitment, dendritic-cell activation, and subsequent T-cell priming. This early immune-priming phase may be followed by suppressive feedback involving hypoxia, tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, PD-1/PD-L1 signaling, and IL-10/TGF-β. Evidence maturity and translational relevance vary across cutaneous neoplasms: clinical use is best established for actinic keratoses, Bowen disease, and superficial or selected low-risk basal cell carcinomas, whereas PDT-based immunotherapy combinations in invasive cutaneous squamous cell carcinoma and melanoma remain predominantly preclinical or exploratory. In cSCC models, ALA-PDT combined with PD-L1 blockade improved control of primary and distant tumors, providing preclinical support for further translational evaluation of checkpoint-based combinations. Preclinical timing studies further suggest that combination efficacy may depend on aligning checkpoint blockade with the post-PDT T-cell activation window. Photosensitizer localization, fluence, irradiance, oxygenation, and treatment schedule may likewise determine whether PDT favors immunogenic priming or excessive tissue injury and suppressive rebound. These findings position PDT as a parameter-tunable local immune-priming platform whose clinical translation should integrate indication-specific selection, treatment-parameter optimization, temporal immune monitoring, rationally timed combination therapy, and prospective clinical validation.