Innate lymphoid cells in pancreatic ductal adenocarcinoma: Immune regulation and therapeutic implications

Over the past two decades, immunotherapy has revolutionized cancer treatment by shifting our strategies to harness the body's own immune system, with the promise of inhibiting or even eliminating tumors through methods that control and enhance immune responses. Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, features an immunosuppressive tumor immune microenvironment (TIME) that serves as the core factor contributing to poor prognosis of patients. Emerging research has unveiled the dual role of innate lymphoid cells (ILCs), acting as tissue-resident innate immune hubs, in PDAC immune regulation through their dynamic plasticity, heterogeneity, and interactions with various adaptive immune cells. This review systematically summarizes the latest research advancements in the developmental plasticity of ILC subsets and their bidirectional regulatory network in PDAC, highlighting the potential value of targeting ILCs to reshape the PDAC TIME. Future research should integrate single-cell multi-omics technologies to dissect the spatiotemporal heterogeneity of ILCs, develop strategies to activate their anti-tumor activity, and explore synergistic approaches combining chimeric antigen receptor (CAR)-NK cell therapy with existing immunotherapies, providing new paradigms for transforming PDAC from an immunologically "cold" tumor to an immune-sensitive one.