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Here, we use photoactivatable multi\u2010inhibitor liposomes (PMILs) as a clinically translatable strategy to immunomodulate and enhance PDAC treatment using FDA\u2010approved agents: minocycline for tumor priming by downregulating Tdp1, benzoporphyrin derivative incorporated into the liposomal bilayer for photodynamic priming (PDP) of the microenvironment, and irinotecan (IRI) for cytotoxicity. PMILs enable light\u2010triggered PDP followed by IRI release. The reduced Tdp1 combined with PDP and IRI acts synergistically to enhance antitumor activity. In an orthotopic PDAC mouse model, dual priming significantly increased intratumoral IRI accumulation while downregulating Tdp1 and ABCG2, two key mediators of IRI resistance. These effects were augmented by immune activation, including increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell infiltration, reduced regulatory T cells, and M2\u2010like macrophage population. This combination achieved sustained local tumor regression, abscopal effects in untreated distant tumors, and a significant improvement in long\u2010term survival (63%). By integrating clinically approved agents with non\u2010overlapping mechanisms within a light\u2010activated delivery platform, this approach enhances IRI efficacy, reprograms the TME, and promotes antitumor immunity, offering a translatable strategy to sensitize PDAC to chemo\u2010 and immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.75291","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:41:40Z","timestamp":1776426100000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Photodynamic Priming and Minocycline Overcome Chemoresistance by Reprogramming the Pancreatic Tumor Immune Microenvironment In Vivo"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6247-2220","authenticated-orcid":false,"given":"Fernanda V.","family":"Cabral","sequence":"first","affiliation":[{"name":"Wellman Center For Photomedicine Massachusetts 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