Introduction: Cholangiocarcinoma (CCA) is a rare, deadly cancer that is characterized by an abundant desmoplastic stroma. Late diagnoses and limited available effective treatments are major problems with this malignancy. Targeting of the tumor microenvironment (TME) has emerged as a potential therapeutic strategy.Areas covered: In this review, we describe the role of the various compartments of the TME in CCA and focus on the preclinical rationale for the development of innovative therapies. Relevant literature was identified by a PubMed search covering the last decade (2010-2020).Expert opinion: Low efficacy of surgery and cytotoxic chemotherapy emphasizes the need for new therapeutic strategies and companion biomarkers. Single-cell RNA sequencing of the stroma is yielding a critical functional characterization of TME in CCA and is paving the way for immunotherapies and cancer-associated fibroblast and extracellular matrix-oriented treatments. We believe that the development of treatments targeting the components of the TME will produce the best results if in combination with cytotoxic chemotherapy. Biomarkers should be developed to define the patient population of interest for each combination strategy.
Keywords: Angiogenesis; cancer-associated fibroblast; cholangiocarcinoma; combined therapy; extracellular matrix; immunotherapy; stroma; therapeutic targets; transcriptomics; tumor microenvironment.