Immune cell metabolic reprogramming in pancreatic cancer: roles in tumor progression and therapeutic strategies

Pancreatic cancer is one of the most lethal malignancies of the digestive system, and its profoundly immunosuppressive tumor microenvironment (TME) represents a major driver of tumor progression and therapeutic resistance. Emerging evidence indicates that metabolic reprogramming profoundly influences the polarization, effector function, survival, and fate of immune cells within the TME, thereby shaping the balance between antitumor immunity and immune escape. However, substantial challenges remain, including the incompletely understood metabolic heterogeneity among distinct immune cell subsets and the limited clinical translation of therapeutic strategies combining metabolic intervention with immunotherapy. In this review, we summarize the metabolic reprogramming characteristics and underlying molecular mechanisms of major immune cell populations in pancreatic cancer, including T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and natural killer (NK) cells, with particular emphasis on their reciprocal interactions with pancreatic cancer progression and the immunosuppressive microenvironment. We further discuss recent advances in metabolism-targeted therapies and immunotherapy, highlighting the therapeutic potential of combination strategies centered on immunometabolic modulation. Finally, we outline current challenges and emerging opportunities in this rapidly evolving field, with the aim of providing a mechanistic framework and translational perspectives for the development of precision therapeutic strategies for pancreatic cancer.