Mechanism and clinical relevance of metabolic-immune cross-talk in pancreatic tumor microenvironment.

Metabolic stress-induced immunosuppression begins as early as the precancerous stage in pancreatic ductal adenocarcinoma (PDAC), increases with disease progression, and is characterized by the abundant suppressive myeloid and lymphoid cells. Metabolic adaptation and reprogramming are critical for the survival and function of tumor-infiltrating immune cells. In particular, cytotoxic T cells and natural killer (NK) cells, the stalwarts of cell-mediated immunity, often fail to adapt to the metabolically distinct pancreatic tumor microenvironment (TME) and thus perform antitumor activities poorly, leading to immune exhaustion, aggressive disease progression, metastasis, and poor immunotherapy outcomes. This review article explores the intricate metabolic-immune crosstalk, mediated by tumor microenvironment-associated factors, that impacts the metabolic fitness and effector functions of infiltrating immune cells, including cytotoxic T cells, NK cells, and myeloid cells that bridge innate and adaptive immunity. In addition, we discuss how genetic, molecular, and stromal factors drive metabolic alterations in nutrient-deficient pancreatic tumors, leading to immune cell dysfunction, impaired cytokine release, and poor antitumor immunity. This review further emphasizes the selective targeting of metabolic stress-driven immunosuppressive pathways, unresolved questions, and future directions, including how spatial nutrient gradients across the TME shape distinct regional immune phenotypes, how metabolic interactions with tumor and immune cells occur, and how tumor-selective metabolic therapies could be engineered to exploit features such as hypoxia and acidosis. Understanding these metabolic interactions is crucial for advancing personalized immunotherapy approaches, including immune checkpoint blockade therapies, CAR-T, and other adoptive immune cell therapies, which could improve clinical outcomes in PDAC patients.