Background <p>Mucosal-associated invariant T (MAIT) cells have been implicated in several malignancies, but their role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aimed to characterize the presence, phenotype, and functional role of MAIT cells in PDAC and explore the underlying regulatory mechanisms.</p> Methods <p>We analyzed human PDAC tissue samples using single-cell RNA sequencing and flow cytometry to evaluate MAIT cell abundance and phenotype. Functional studies were performed in MR1-deficient (<i>Mr1</i>^{<i>−/−</i>}) mice to assess the impact of MAIT cell deficiency on tumor-associated macrophage polarization. Cytokine profiling and signaling analyses were used to investigate mechanisms of MAIT cell activation within the tumor microenvironment.</p> Results <p>MAIT cells were significantly enriched in PDAC tissues and associated with poor patient survival. Further studies inMR1-deficient (<i>Mr1</i>^{<i>−/−</i>}) mice demonstrated that the absence of MAIT cells markedly attenuated M2 macrophage polarization. Mechanistically, tissue-resident MAIT cells secreted higher levels of CSF-1 versus circulating subsets. This phenomenon suggests that MAIT cells may be reprogrammed by the tumor microenvironment. Building on this, we discovered that Ttumor-derived TL1A activated MAPK signaling in MAIT cells, potentiating CSF-1 secretion.</p> Conclusions <p>Our findings reveal a novel TL1A-MAIT-CSF-1 axis that drives immunosuppression in PDAC by reprogramming innate immune responses. Targeting MAIT cells or TL1A signaling may represent a promising therapeutic strategy to improve immunotherapy efficacy in PDAC.</p>