Our study here comprehensively characterized that TGIF1 functions as a PDAC tumor suppressor, blocking the progression of KrasG12D-initiated neoplasms, inhibiting EMT, modifying cancer epigenetics and tumor immune microenvironment, as well as restricting the activation of Has2/CD44 signaling pathway in facilitating distant metastasis. The gene discussed is TGIF1; the disease is cancer.