Mechanisms and Therapeutic Strategies for Chemoresistance in Hepatobiliary and Pancreatic Malignancies

Abstract

Hepatobiliary and pancreatic (HPB) malignancies— including hepatocellular carcinoma (HCC), cholangiocarcinoma/biliary tract cancers (BTC), and pancreatic ductal adenocarcinoma (PDAC)—remain among the most lethal solid tumors. Although systemic regimens have improved over the past decade, intrinsic and acquired chemoresistance continues to drive early progression, relapse, and limited durability of response. Resistance in HPB tumors is multifactorial and arises from tumor cell– intrinsic programs (drug transport and metabolism, DNA damage response, apoptosis escape, epithelial– mesenchymal transition and cancer stem cell persistence) as well as tumor microenvironment– mediated protection (desmoplastic stroma, hypoxia, immune suppression, and restricted drug penetration). In parallel, a wave of biomarker-guided therapies (e.g., FGFR2/IDH1-targeted agents in cholangiocarcinoma; PARP inhibition in germline BRCA-mutant PDAC) and chemo-immunotherapy combinations (e.g., PD-L1/PD-1 blockade with gemcitabine/cisplatin in BTC) has begun to reshape practice. This review synthesizes key mechanisms of chemoresistance across HPB malignancies, maps these mechanisms to actionable therapeutic strategies, and highlights clinical evidence that informs current decision-making. We also discuss translational gaps and practical directions for overcoming resistance, including adaptive combinations, stromal and metabolic reprogramming, and integration of molecular profiling with dynamic biomarkers.