Overcoming therapeutic resistance in biliary tract cancer: from resistance mechanisms to dynamic precision oncology - a narrative review.

INTRODUCTION: Biliary tract cancer (BTC) is a biologically heterogeneous and highly aggressive malignancy with limited therapeutic options and poor survival. Although chemotherapy, targeted therapies, and immune checkpoint inhibitors have improved treatment outcomes, intrinsic and acquired resistance remain the major barriers to durable clinical benefit. AREAS COVERED: A comprehensive literature search of PubMed, Embase, and Web of Science was conducted for studies published through June 2026. This narrative review summarizes current mechanisms of therapeutic resistance in BTC, including genetic evolution, clonal selection, epigenetic plasticity, cancer stem cells, non-genetic adaptive resistance, metabolic reprogramming, and tumor microenvironment-mediated immune evasion. Emerging strategies to overcome resistance are discussed, including rational combination therapies based on acquired vulnerability, next-generation targeted therapies, tumor microenvironment remodeling, immunotherapy optimization, epigenetic and metabolic interventions, and precision oncology supported by liquid biopsy and dynamic molecular monitoring. EXPERT OPINION: BTC management is evolving toward biologically informed precision oncology. Integrating comprehensive molecular profiling, longitudinal liquid biopsy, biomarker-guided patient selection, and mechanism-based combination therapies will enable dynamic treatment adaptation and may improve long-term outcomes. Advances in multi-omics, artificial intelligence, and biomarker-driven clinical trial designs are expected to further accelerate personalized therapeutic strategies.