{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:24Z","timestamp":1789448544406,"version":"build-2803163510"},"reference-count":78,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Malignant melanoma presents formidable therapeutic challenges due to optical shielding and free-radical scavenging by endogenous melanin, profound tumor microenvironment hypoxia, and aggressive metastatic dissemination, rendering conventional photodynamic therapy (PDT) clinically immature. This narrative review comprehensively synthesizes literature across PubMed\/MEDLINE, Scopus, and Web of Science evaluating photochemical mechanisms, photosensitizing agents, bioengineered drug delivery systems, and adjacent light-triggered strategies. Preclinical evidence demonstrates that third-generation photosensitizers, targeted organic\/inorganic nanoparticles, and transdermal dissolving microneedle (MN) arrays effectively bypass the stratum corneum, enhance drug bioavailability, and alleviate hypoxia-mediated treatment resistance. Furthermore, femtosecond two-photon PDT converts melanin into an active energy-transfer mediator, while nanotechnology-driven photoimmunotherapy (PIT) triggers immunogenic cell death (ICD) and systemic CD8+ cytotoxic T-lymphocyte activation to induce abscopal regression of un-irradiated distant metastases. Nevertheless, critical translational bottlenecks persist, including an overwhelming reliance on static two-dimensional (2D) cell cultures, a lack of validated prognostic or predictive biomarkers, and a complete absence of randomized controlled clinical trials. Ultimately, advancing melanoma photomedicine from bench to bedside requires standardized photophysical dosimetry, systematic evaluation in multicellular three-dimensional (3D) tumor spheroids, and prospective clinical trials defining its role in multimodal dermato-oncology.<\/jats:p>","DOI":"10.3390\/ijms27188156","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Overcoming Biophysical Barriers in Melanoma Photomedicine: From Photodynamic Therapy to Smart Nanodelivery and Photoimmunotherapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4616-7753","authenticated-orcid":false,"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, 35128 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, 35128 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\/0000-0002-4575-0548","authenticated-orcid":false,"given":"Marcodomenico","family":"Mazza","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"}]},{"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, 35128 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, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2147\/CCID.S401206","article-title":"Global Trends and Research Progress of Photodynamic Therapy in Skin Cancer: A Bibliometric Analysis and Literature Review","volume":"16","author":"Sun","year":"2023","journal-title":"Clin. 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