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This narrative review synthesized literature from major databases (2010\u20132025) to comprehensively evaluate PDT\u2019s molecular mechanisms, innovative optimization protocols, and clinical efficacy across actinic keratosis (AK), field cancerization, Bowen\u2019s disease (BD), basal cell carcinoma (BCC), and invasive squamous cell carcinoma (cSCC). The evidence highlights frontline clinical maturity and excellent cosmetic outcomes for superficial lesions (AK, field cancerization, superficial BCC, and BD), with daylight PDT offering a virtually painless alternative for widespread dysplasia. However, therapeutic reliability decreases in thick nodular, pigmented, or high-risk lesions due to optical barriers and tissue hypoxia. To overcome these limitations, advanced physical and chemical enhancements\u2014such as ablative fractional lasers, iron chelators, epigenetically enhanced PDT (ePDT), and targeted nanocarriers\u2014are actively reshaping drug delivery and cellular susceptibility. Furthermore, cyclic PDT serves as an indispensable tissue-sparing intervention for organ transplant recipients and Gorlin syndrome patients. In conclusion, while PDT is highly effective for superficial neoplasias, precise histopathological stratification and the integration of nanomedicine are critical to overcoming current biological barriers in aggressive dermatological malignancies.<\/jats:p>","DOI":"10.3390\/ijms27146396","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Photodynamic Therapy for Keratinocytic Precancerous Lesions and Non-Melanoma Skin Cancer: A Narrative Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Francesco","family":"Russano","sequence":"first","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-2594","authenticated-orcid":false,"given":"Luigi","family":"Dall\u2019Olmo","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, 35020 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9709-977X","authenticated-orcid":false,"given":"Davide","family":"Brugnolo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, 35020 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9594-5178","authenticated-orcid":false,"given":"Francesco","family":"Callegarin","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-8014","authenticated-orcid":false,"given":"Paolo","family":"Del Fiore","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Caminiti","sequence":"additional","affiliation":[{"name":"Casa di Cura Caminiti, Villa San Giovanni, 89018 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Rastrelli","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, 35020 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-8445","authenticated-orcid":false,"given":"Simone","family":"Mocellin","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padua, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, 35020 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chen, Q., Bai, M., Lu, M., Chen, J., Wang, S., Sun, P., Li, L., and Cai, H. 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