Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.

Biliary and pancreatic malignant tumors refer to biliary tract carcinoma (BTC) and pancreatic cancer (PC), among which BTC mainly includes cholangiocarcinoma (CCA) and gallbladder cancer (GBC), and their prognosis is poor because of the lack of effective early diagnostic methods. Although surgical resection is the preferred method for a cure, treatment options are limited for patients with advanced tumors. Therefore, the exploration of other new treatment methods is urgently needed. Currently, metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. As an indispensable part of metabolic reprogramming in tumor cells, amino acid (AA) metabolic reprogramming provides an energy source for tumor cells and participates in regulating the tumor microenvironment (TME). Moreover, as important intrinsic myeloid cells, macrophages play indispensable physiological roles in malignant tumor progression. In the TME, tumor cells can not only induce peripheral immune tolerance by releasing extracellular signals but also compete with tumor-associated macrophages (TAMs) for AAs and release the resulting downstream metabolites into the TME, directly targeting and damaging immune cells and influencing macrophage polarization. Consequently, a more profound understanding of the function of AA metabolic reprogramming in biliopancreatic malignancies and their associated macrophage polarization holds the potential to facilitate the development of effective strategies for early diagnosis, prognostic assessment and targeted therapy in patients with biliopancreatic malignancies. In this paper, we review the impact of AA metabolic reprogramming on the occurrence and development of biliary and pancreatic malignant tumors, summarize the relevant mechanisms of AA metabolic reprogramming on the polarization of TAMs, and provide new therapeutic targets for AA metabolic therapies and immunotherapies for biliary and pancreatic malignant tumors.