Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with median survival rarely exceeding one year post-diagnosis. Conventional therapeutic approaches beyond surgical resection offer marginal clinical improvements, and contemporary immunotherapeutic strategies have demonstrated limited efficacy in PDAC treatment. This investigation evaluated the therapeutic potential of combining neoadjuvant visudyne-mediated photodynamic therapy (PDT) with anti-PD1 immune checkpoint inhibition using murine orthotopic KPC models. The combination therapy produced complete tumor eradication in 50% of subjects in the orthotopic model and 37. 5% in the bilateral subcutaneous model. Our mechanistic analysis reveals that PDT exerts multi-faceted cytotoxic effects, targeting not only malignant PDAC cells but also immunosuppressive monocytic and lymphocytic populations within the tumor microenvironment. PDT disrupts the immunosuppressive axis between dendritic cells and regulatory T cells, which represents a mechanism of immune tolerance in PDAC. Additionally, PDT modulates systemic immune suppression by altering tumor-derived cytokine profiles, particularly within the splenic compartment. The PDT-mediated reprogramming of both local and systemic immunosuppression creates a permissive environment for enhanced anti-PD1 therapeutic efficacy. This synergistic effect is characterized by increased cytotoxic CD8+ T cell activation in draining lymph nodes and an improved CD8+ T cell to regulatory T cell ratio within tumor tissues. These results demonstrate PDT's distinctive immunomodulatory capabilities and establish its potential as a neoadjuvant treatment to enhance immune checkpoint blockade effectiveness in a preclinical pancreatic cancer model. Citation Format: Derek Allen, Mohammad Ahsan Saad, Tessa D. Van Bergen, Jimena Nicolás Morala, Zhiming Mai, Harrison Roberts, Tayyaba Hasan. Neoadjuvant photodynamic therapy potentiates anti-PD1 therapy in a murine pancreatic cancer model abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B019.
Allen et al. (2025) studied this question.