Stratifying cholangiocarcinoma: tumor microenvironment, molecular drivers, and novel immunotherapeutic approaches.

Cholangiocarcinoma (CCA) is an epithelial cell cancer of the biliary tract. CCA can be further classified into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA) depending on the anatomical location. Until recently, the treatment for advanced CCA has remained highly reliant on chemotherapy, with gemcitabine plus cisplatin used in first-line treatment. Recent developments have led to the addition of immune checkpoint blockade (ICB) to the chemotherapy regimen, highlighting the promising potential of immunotherapies for CCA treatment. Despite these developments, most patients still do not benefit from current treatments, and response rates to ICB monotherapy remain modest. This underscores the need to develop more effective immunotherapeutic strategies. A major obstacle to this is the highly heterogenous nature of the disease. CCA tumors exhibit high inter-tumor heterogeneity in terms of anatomical locations, driver mutations, etiologies, and tumor microenvironment (TME) composition, making each patient immunologically distinct and difficult to benefit from a one-size-fits-all approach. There is a need to stratify patients according to individual disease status to identify immunotherapies and combination therapies that are most beneficial to them. Here we describe the different ways inter-tumor heterogeneity may arise in CCA, including stromal cell abundance, anatomical location, driver mutations, etiologies, TME profile, and tertiary lymphoid structure (TLS) presence. We also discuss what these factors mean to the immune microenvironment and their potential to be used as biomarkers. Careful stratification of patients is crucial in designing personalized medicine to improve survival outcomes and treatment efficacy for CCA patients.