Neoadjuvant photodynamic therapy alters the local and systemic immune microenvironment and synergizes with anti-PD1 treatment in a murine pancreatic cancer model

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, with most patients surviving less than one year after diagnosis. Unlike other cancers which have seen improvement in the past decade, PDAC remains resistant to immunotherapy. We investigated whether neoadjuvant photodynamic therapy (PDT) could enhance anti-PD1 efficacy in a murine PDAC model. Combined PDT and anti-PD1 therapy achieved substantial survival and, in some instances, complete recovery from both orthotopic and subcutaneous tumors. Mechanistically, PDT eliminated both tumor cells and immunosuppressive monocytic and lymphocytic populations while disrupting dendritic cell-regulatory T cell interactions critical for immune tolerance. Systemically, PDT reduced splenic immunosuppression through altered cytokine profiles. This dual local and systemic immune reprogramming enhanced anti-PD1 effectiveness, evidenced by increased cytotoxic CD8+ T cells in lymph nodes and an improved cytotoxic to regulatory T cell ratio within tumors. These findings highlight PDT's unique immunomodulatory properties and potential to overcome checkpoint blockade resistance in pancreatic cancer.