Advances in deciphering intratumoral versus peritumoral heterogeneity of infiltrating lymphocytes in pancreatic cancer: a spatial perspective

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a profoundly immunosuppressive and spatially heterogeneous tumor microenvironment. Recent research has focused on the distinct topographic distribution of tumor-infiltrating lymphocytes (TILs) across intratumoral and peritumoral compartments. This review synthesizes the latest advances, delineating the distribution, functional states, and ontogeny of region-specific TIL subsets, and dissects how spatial heterogeneity fuels disease progression and resistance to immunotherapy. We further explore the reciprocal crosstalk between immunosuppressive stroma and lymphocyte heterogeneity, highlight prevailing technical and conceptual challenges, and outline emerging technologies poised to shape the next phase of discovery. This work provides a comprehensive roadmap to accelerate translation in PDAC immuno-oncology.