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PDAC, the most common form of pancreatic cancer, is highly lethal and poorly responsive to immunotherapy due in part to its dense fibrosis and immunosuppressive tumor microenvironment. Immune cells within PDAC often become pro-tumoral, further limiting anti-cancer responses. RNASET2, a conserved stress-response gene with strong tumor-suppressive activity, can recruit and activate M1 macrophages when overexpressed in cancer cells. This positions RNASET2 as a potential endogenous “alarmin” that alerts the innate immune system to tumor development. This project investigates whether RNASET2 can enhance anti-tumor immunity in PDAC by boosting NK and CD8+ T-cell activity, reducing immunosuppression, and modulating fibrosis. It will test RNASET2 alone or in combination with anti-fibrotic strategies, characterize the PDAC immune microenvironment in mouse models and patient samples, and assess RNASET2 as a potential immunomodulatory effector. The study aims to clarify how fibrosis and immune cells interact in PDAC and how alarmin-like molecules might improve responses to immunotherapy.