Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy

Introduction: Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of patients present at an advanced stage. CCAs are heterogeneous tumors and currently available standard systemic therapy options are of limited effectiveness. Immune checkpoint inhibition (ICI) has transformed cancer therapy across a spectrum of malignancies. However, the response rate to ICI has been relatively disappointing in CCAs owing to its desmoplastic tumor microenvironment (TME). Areas covered: Tumor microenvironment of CCAs consists of innate and adaptive cells, stromal cells, and extracellular components (cytokines, chemokines, exosomes, etc.). This intricate microenvironment has multiple immunosuppressive elements that promote tumor cell survival and therapeutic resistance. Accordingly, there is a need for the development of effective therapeutic strategies that target the TME. Herein, we review the components of the CCA TME, and potential therapies targeting the CCA TME. Expert opinion: CCAs are desmoplastic tumors with a dense tumor microenvironment. An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.