Metabolic reprogramming in cholangiocarcinoma cancer stem cells: Emerging therapeutic paradigms

Cholangiocarcinoma (CCA) is an aggressive malignancy characterized by limited therapeutic options and poor prognosis, largely attributed to the presence of cancer stem cells (CSCs). These CSCs serve as pivotal drivers of tumor heterogeneity, chemotherapy resistance, and disease recurrence. CSCs in CCA exhibit remarkable plasticity, a characteristic sustained through metabolic state alterations and intricate interactions with the tumor microenvironment (TME), which collectively enhance their self-renewal and survival potential. While advancements have been made in understanding metabolic reprogramming of CCA CSCs, translating these findings into clinical applications encounters significant challenges, including insufficient target specificity, complex metabolic heterogeneity, and the profound complexity of the TME. This review provides a systematic evaluation of metabolic reprogramming mechanisms in CCA CSCs, with critical analysis of stemness-maintaining signaling pathways, oxidative phosphorylation (OXPHOS), nutrient utilization, metabolic crosstalk within the TME, autophagy regulation, and ferroptosis resistance. We emphasize emerging strategies to therapeutically target the interconnected metabolic networks essential for CSC functionality and survival, with the goal of establishing a theoretical basis for innovative precision therapies to enhance clinical outcomes for CCA patients.