Role of the stromal and immune microenvironment in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) represents one of the deadliest malignancies with an overall 5-year survival rate of 10%. For the past decades, surgery and chemotherapy have been the only option for early and late-stage disease, respectively. In more recent years, the characterization of the genomic landscape of iCCA has identified several "druggable" oncogenic drivers and led to the FDA approval of the first targeted therapies, including FGFR and IDH inhibitors, for the second-line therapy of genetically defined patients' subsets. Nonetheless, patients treated with these therapies quickly progress due to the onset of resistance. At a moment when immune checkpoint inhibitors (ICIs) are profoundly altering the approach to cancer treatment, their use in combination with chemotherapy has only modestly improved survival of iCCA, with more than two thirds of patients showing intrinsic resistance. The aggressive and refractory nature of this cancer is often attributed to its intricate tumor microenvironment (TME), but the exact interplay between tumoral cells and other TME components (i.e., immune cells, cancer-associated fibroblasts, endothelial cells) as well as the molecular and cellular mechanisms mediating tumor progression and therapeutic resistance remains overall poorly understood. In this review article, we will discuss the important role of the stromal and immune TME of iCCA and how its characterization has shaped patient stratification and molecular classes. We will describe recent findings supporting unique genotype-immunophenotype relationships in iCCA, and the existence of functionally heterogenous subsets of cancer-associated fibroblasts. The ultimate goal is to provide an exhaustive overview of current knowledge and a provoking discussion of therapeutic implications and future directions.