Adrenomedullin Inhibits the Efficacy of Combined Immunotherapy and Targeted Therapy in Biliary Tract Cancer by Disrupting Endothelial Cell Functions

Abstract

The global incidence of biliary tract cancer (BTC) is on the rise, presenting a substantial healthcare challenge. The integration of immune checkpoint inhibitors (ICIs) with molecularly targeted therapies is emerging as a strategy to enhance immune responses. However, the efficacy and underlying mechanisms of these treatments in BTC are still largely unexplored. In this study, tissue samples from 19 BTC patients treated with camrelizumab and apatinib were analysed using the NanoString 289-panel to identify key molecular biomarkers. Comparative analyses and subsequent experimental validations, including cell-based assays and histopathological examinations, identified adrenomedullin (ADM) as a critical molecular marker associated with treatment efficacy and poor prognosis. ADM has been shown to promote BTC cell proliferation, migration and angiogenesis, primarily by interacting with vascular endothelial growth factor (VEGF) and increasing AKT phosphorylation. Furthermore, ADM disrupts endothelial cell barrier function via the calcitonin receptor-like receptor (CRLR) and vascular endothelial (VE)-cadherin signalling pathway. Preclinical inhibition of ADM or CRLR resulted in suppressed tumour growth. Additionally, elevated ADM expression was correlated with increased tumour-infiltrating immune cells and higher immune checkpoint expression. These findings suggest that ADM plays a pivotal role in resistance to immunotherapy and anti-angiogenic treatment in BTC, and thus, targeting ADM may offer a promising therapeutic approach to enhance treatment efficacy.