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Photodynamic therapy (PDT) is a well\u2010established, nonscarring treatment for nonmelanoma cancers such as early squamous precancers (actinic keratoses, AK), squamous carcinoma in\u00a0situ, and superficial basal cell carcinoma (BCC). PDT can be painful during illumination and has relatively poor efficacy for thick lesions. However, these disadvantages could be ameliorated if newly recognized PDT effects on immunity were fully understood and harnessed. In this review, we highlight basic and translational studies on effects that locally administered PDT exerts on the immune system. On the one hand, PDT stimulates an anti\u2010tumor immune response observable as peritumoral infiltration of innate and adaptive immune cells and activation of cytotoxic T cells both locally and in circulating blood. On the other hand, PDT generates systemic immunosuppression mediated by the release of subcellular microvesicle particles (MVP); the latter may be blocked by using acid sphingomyelinase (aSMase) inhibitors. The ultimate goal must be to balance two opposing forces, that is, to limit PDT\u2010induced immunosuppression while promoting PDT\u2010induced regression of tumors so as to favor a long\u2010term anti\u2010tumor immune response.<\/jats:p>","DOI":"10.1111\/php.70008","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T00:29:25Z","timestamp":1751675365000},"page":"533-547","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Immunomodulatory effects of photodynamic therapy for skin cancer: Potential strategies to improve treatment efficacy and tolerability"],"prefix":"10.1111","volume":"102","author":[{"given":"Mark P.","family":"Ortenzio","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University  Dayton Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Dermatology Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering Cleveland Clinic  Cleveland Ohio USA"},{"name":"Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7232-1039","authenticated-orcid":false,"given":"Jeffrey B.","family":"Travers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University  Dayton Ohio USA"},{"name":"Department of Dermatology Boonshoft School of Medicine, Wright State University  Dayton Ohio USA"},{"name":"Dayton V.A. 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