Rewiring immunometabolism in hepato-biliary-pancreatic cancers: Unraveling TME-mediated metabolic suppression and advancing next-generation immunotherapeutic approaches.

Hepato-biliary-pancreatic cancers, notorious for their pronounced heterogeneity and poor prognosis, continue to be a dominant factor in cancer-related deaths globally. Although immunotherapy has dramatically reshaped the cancer treatment landscape, its efficacy in these malignancies remains suboptimal due to the intense immunosuppression in the tumor microenvironment (TME) stemming from metabolic dysregulation. This review provides an in-depth analysis of the fundamental mechanisms of immunometabolic suppression. It highlights the strategies employed by tumor cells to compete with immune cells for nutrients, the accumulation of inhibitory metabolitessuch as lactate and adenosine, and disrupt pivotal metabolic pathways in CD8+ T, NK, and myeloid cells, ultimately leading to functional depletion. The novelty of this work lies in its systematic classification of these metabolic vulnerabilities and the introduction of a tripartite approach to address them: nutrient redistribution, metabolite scavenging, and enhancement of immune cell intrinsic metabolism. This approach aims to complement the next generation of immunotherapies, converting immunologically "cold" tumors into "hot" ones. Additionally, the review emphasizes the potential of integrating multi-omics profiling, artificial intelligence, and biomarker-guided personalized therapy as avenues to overcome resistance and enhance clinical efficacy. By viewing the challenge of therapy resistance through a metabolic perspective, this study not only enriches our foundational understanding of tumor-immune interactions but also presents a practical framework for designing highly efficacious combination therapies, representing a crucial advancement in the management of these formidable cancers.