Role of the stromal and immune microenvironment in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is one of the deadliest malignancies, with an overall 5-year survival rate of approximately 10%. For decades, surgery and chemotherapy have represented the only treatment options for early- and late-stage disease, respectively. More recently, characterisation 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 second-line treatment in genetically defined patient subsets. Nonetheless, most patients treated with these therapies rapidly develop resistance and eventually experience disease progression. At a time when immune checkpoint inhibitors (ICIs) are profoundly reshaping cancer treatment, their use in combination with chemotherapy has yielded only modest survival benefits in iCCA, with more than two-thirds of patients exhibiting intrinsic resistance. The aggressive and refractory nature of this cancer is often attributed to its intricate tumour microenvironment (TME); however, the complex interplay between tumour cells and other TME components (i.e. immune cells, cancer-associated fibroblasts, and endothelial cells), as well as the molecular and cellular mechanisms driving tumour progression and therapeutic resistance, remain poorly understood. In this review, we discuss the critical role of the stromal and immune TME in iCCA and how its characterisation has informed patient stratification and molecular classification. We also describe recent findings supporting distinct genotype-immunophenotype relationships in iCCA, as well as the existence of functionally heterogeneous subsets of cancer-associated fibroblasts. Ultimately, this review aims to provide a comprehensive overview of current knowledge while stimulating discussion on therapeutic implications and future research directions.