AUTHOR=Xue Jingnan , Zhang Longhao , Zhang Kai , Wu Yu , Zhou Kai , Lu Xin 

TITLE=Metabolic collusion driving immune evasion in cholangiocarcinoma: unmasking the dual control of the immuno-metabolic microenvironment

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1697056

DOI=10.3389/fimmu.2025.1697056

ISSN=1664-3224

ABSTRACT=Cholangiocarcinoma represents an aggressive malignancy with poor prognosis, particularly for intrahepatic Cholangiocarcinoma. Despite recent advancements in chemotherapy and immune checkpoint blockade therapies, survival outcomes remain suboptimal. A key obstacle in treating Cholangiocarcinoma is its immune exclusion and resistance to Cholangiocarcinoma, which is influenced by metabolic reprogramming within the tumor microenvironment. This review explores the dual control of metabolism and immunity in Cholangiocarcinoma, highlighting the intricate interplay between metabolic pathways (e.g., glycolysis, lactate accumulation, fatty acid oxidation) and immune evasion mechanisms. We examine how bile acid signaling, hypoxia, and stromal interactions shape Cholangiocarcinoma’s immune landscape, facilitating tumor progression and immune resistance. Moreover, we discuss emerging therapeutic strategies that target metabolic vulnerabilities to “convert” immune-excluded Cholangiocarcinoma into a more immunologically responsive state. These strategies include metabolic inhibitors targeting lactate, amino acid catabolism, and fatty acid metabolism, as well as approaches to modulate bile acid signaling. We propose that combining metabolic reprogramming with immune checkpoint blockade therapies holds significant promise in enhancing immune responses and improving therapeutic outcomes for Cholangiocarcinoma patients. This review provides a comprehensive framework for future research and clinical trials, aiming to bridge the gap between metabolic insights and immunotherapy in Cholangiocarcinoma treatment.