Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dense desmoplastic stroma and an immunosuppressive tumor microenvironment (TME), both of which limit therapeutic efficacy. Immune evasion and fibrosis within the TME create substantial barriers to effective treatment. Key immunosuppressive cell populations, such as regulatory T cells and Arginase-1 (Arg1)-expressing M2 macrophages, suppress anti-tumor immunity primarily by inhibiting cytotoxic T cell activity. A critical enzyme regulating the immunosuppressive TME is phosphatidylinositol 3-kinase δ (PI3Kδ), which enhances regulatory T cell activation and migration while driving cytotoxic T cell exhaustion. Additionally, lysophosphatidic acid (LPA) signaling, driven by the enzyme autotaxin (ATX), impairs CD8+ T cell activation and proliferation. Elevated ATX levels in PDAC patients not only reinforce immune suppression but also promote fibroblast and immune cell migration, further exacerbating tumor fibrosis.

Here, we used two clinically relevant ATX and PI3Kδ inhibitors to simultaneously enhance anti-tumor immunity and remodel the tumor microenvironment (TME). To investigate the role of PI3Kδ and ATX in patient prognosis, we first analyzed human PDAC tissue microarrays. Additionally, we utilized a genetically defined KrasG12D-driven pancreatic cancer mouse model (KPC mouse model) and an orthotopic mouse model, followed by histological examination and immunohistochemistry stainings of dissected tissues.

The combination of ATX/PI3Kδ treatment improved immune response, diminished fibrosis, and increased activated cytotoxic T cells, ultimately leading to decreased tumor progression and prolonged survival in PDAC. Moreover, combination of ATX/PI3Kδ inhibitors with chemo- and immunotherapy further extended survival.

Our findings highlight the potential of this multitargeted approach to enhance anti-tumor immunity and improve therapeutic outcomes.