This is a prospective, non-randomized, open-label, single-center phase II clinical trial. It aims to evaluate the efficacy and feasibility of using patient-derived tumor organoid drug sensitivity testing (ODST) to guide personalized systemic therapy for patients with unresectable biliary tract cancers (BTC). A total of 88 eligible patients will be enrolled and grouped based on patient preference into either the ODST-guided group or the control group (standard therapy). Tumor tissues obtained via biopsy will be used to establish organoid cultures. Drug sensitivity testing will be performed on a panel of approved regimens (including GC, GEMOX, Durvalumab+GC, Pembrolizumab+GC, and Toripalimab+Lenvatinib+GEMOX) to identify the most effective treatment. Patients for whom organoid testing fails or results are unavailable within one month will receive standard therapy. The primary endpoints are Objective Response Rate (ORR) and Progression-Free Survival (PFS). Secondary endpoints include Overall Survival (OS) and safety profiles. The study seeks to provide a novel, personalized treatment strategy to improve outcomes for patients with advanced BTC.