Antibody-drug conjugates as promising platform for intrahepatic cholangiocarcinoma: molecular insights, drug-delivery challenges, and emerging therapeutic targets.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary hepatic malignancy with increasing incidence, poor prognosis, recurrence, and limited therapies. Currently, surgical resection remains the only potentially curative treatment for iCCA. The main challenge, even after surgery, is that small or poorly cellular liver tumors may recur a year later if minimal residual disease goes undetected. Additionally, the majority of chemotherapy and targeted therapies have modest clinical benefit due to tumor heterogeneity and therapeutic resistance. Antibody-drug conjugates (ADCs) have recently emerged as a promising targeted therapeutic platform by combining the tumor specificity of monoclonal antibodies with highly potent cytotoxic payloads, thereby enabling selective drug delivery while minimizing systemic toxicity. This review comprehensively summarizes the molecular landscape of iCCA relevant to ADC development and discusses clinically significant targets, including HER2, FGFR2, TROP2, Claudin-1, MUC1, EpCAM, and EGFR. The structural and functional significance of ADC components, including antibodies, linkers, and payloads, are also discussed in relation to therapeutic efficacy and safety. Furthermore, current preclinical and clinical progress involving ADC-based therapies for iCCA and related cholangiocarcinoma is highlighted. Tumor heterogenicity, drug resistance, desmoplastic tumor microenvironment, and low antigen binding are among the primary barriers to the development of ADCs for iCCA that are critically discussed. Additionally, the prospects for the next generation, including bispecific ADCs and dual-payload conjugates for iCCA, were explored. Collectively, ADCs represent a rapidly evolving precision oncology platform with considerable potential to improve therapeutic outcomes and future management strategies for patients with iCCA.