mTOR signaling in cholangiocarcinoma: mechanistic insights and therapeutic opportunities

Cholangiocarcinoma (CCA) is a clinically and molecularly heterogeneous malignancy originating from the biliary epithelium. It represents the second most common primary liver cancer after hepatocellular carcinoma (HCC). Despite advances in understanding CCA pathobiology and improving diagnostic modalities, its global incidence and mortality continue to rise. Most patients are diagnosed at advanced stages, which are characterized by frequent recurrence, metastasis, and therapeutic resistance, leading to poor clinical outcomes. The mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cell growth, metabolic reprogramming, survival, and autophagy; its dysregulation significantly contributes to CCA initiation and progression. However, the precise roles of mTOR signaling across different CCA subtypes remain incompletely understood, and conflicting evidence exists regarding its context-dependent functions in tumor progression and therapeutic response. This review provides a comprehensive overview of recent advances in mTOR research in CCA, focusing on its involvement in metabolic reprogramming, malignant phenotypes, autophagy, apoptosis, and treatment resistance. Furthermore, current limitations and knowledge gaps in targeting mTOR signaling are discussed, alongside emerging therapeutic strategies, such as mTOR inhibitors, combination approaches, and natural small-molecule modulators. Finally, future research directions and the potential of mTOR-centered interventions to improve clinical outcomes in CCA are highlighted.