Photodynamic Priming and Minocycline Overcome Chemoresistance by Reprogramming the Pancreatic Tumor Immune Microenvironment In Vivo

ABSTRACT Overcoming drug resistance in pancreatic ductal adenocarcinoma (PDAC) remains a major challenge due to dense fibrotic stroma, DNA repair–mediated resistance, drug efflux mechanisms, and an immunosuppressive tumor microenvironment (TME). Here, we use photoactivatable multi‐inhibitor liposomes (PMILs) as a clinically translatable strategy to immunomodulate and enhance PDAC treatment using FDA‐approved 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‐triggered 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 ⁺ T‐cell infiltration, reduced regulatory T cells, and M2‐like macrophage population. This combination achieved sustained local tumor regression, abscopal effects in untreated distant tumors, and a significant improvement in long‐term survival (63%). By integrating clinically approved agents with non‐overlapping mechanisms within a light‐activated delivery platform, this approach enhances IRI efficacy, reprograms the TME, and promotes antitumor immunity, offering a translatable strategy to sensitize PDAC to chemo‐ and immunotherapy.