Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the biliary epithelium, and its complex tumor microenvironment (TME) plays a crucial role in the disease’s progression and therapeutic resistance. Recent insights into the unique characteristics of the CCA TME have illuminated the intricate interactions between tumor cells, stromal elements, and immune components. These interactions not only facilitate tumor growth but also impact the overall prognosis and response to therapy.
A defining feature of the CCA microenvironment is its desmoplastic stroma, which comprises various cell types, including cancer-associated fibroblasts (CAFs), immune cells, and extracellular matrix (ECM) components. The ECM undergoes significant remodeling in CCA, which is essential for maintaining the structural integrity of the TME and influencing tumor behavior. Such alterations can be attributed to various secreted factors released by the cancer cells and CAFs that modify the ECM’s composition and mechanical properties.
CAFs are recognized as one of the most abundant cell types within the CCA TME. These fibroblast-like cells morphologically and functionally differ from normal fibroblasts. Traditionally characterized by their expression of alpha-smooth muscle actin (αSMA), CAFs exhibit a range of activities that contribute to CCA development and progression. Their recruitment into the TME is prompted by signals such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β), which in turn stimulate their proliferation and activation.
The transcriptomic profiling of CAF subpopulations in intrahepatic cholangiocarcinoma (iCCA) has revealed distinct classes: myofibroblastic CAFs, vascular CAFs, and inflammatory CAFs. Myofibroblastic CAFs are enriched in extracellular matrix-related genes and contribute to ECM stiffness, which is critical for tumor growth and invasion. Vascular CAFs express high levels of cytokines and growth factors and are implicated in promoting angiogenesis and lymphangiogenesis within the TME. The dynamic interactions between CAFs and tumor cells enhance processes such as chemoresistance, immune evasion, and metastatic spread.
The role of the ECM in CCA is particularly pronounced due to its contribution to the mechanical and biochemical cues that influence cancer cell behavior. The CCA ECM not only supports tumor architecture but also serves as a reservoir for signaling molecules that regulate cell proliferation, migration, and invasion. Proteins such as periostin, tenascin C, and osteopontin, which are typically overexpressed in the CCA microenvironment, play significant roles in tumor progression by modulating signaling pathways involved in cell survival and proliferation.
Periostin has been identified as a key player in CCA development. It mediates interactions between CAFs and tumor cells, thereby promoting cancer-associated signaling cascades such as the PI3K–AKT pathway, which supports cell survival and enhances metastatic potential. The secretion of periostin by cancer cells can also lead to the recruitment of tumor-associated macrophages (TAMs), further complicating the immune landscape of the TME. Tenascin C, another ECM component, promotes cell proliferation in both tumor and stromal cells by engaging in various signaling pathways, including the Wnt–MAPK pathway.
The interplay between tumor cells and the immune system within the TME presents a complex duality. While innate immunity attempts to combat tumor growth, chronic activation can lead to a state of immune suppression. Tumor-associated macrophages, for instance, exhibit plasticity and can adopt pro-tumorigenic roles, which are often correlated with poor patient prognosis. The influence of myeloid-derived suppressor cells (MDSCs) within the TME also highlights the mechanisms by which tumors evade immune surveillance, further underscoring the need for therapies targeting these pathways.
Adaptive immunity’s role in CCA appears limited, with many tumors exhibiting low levels of tumor-infiltrating lymphocytes. Notably, the presence of CD8+ cytotoxic T cells is often associated with better overall survival rates, indicating the potential for immunotherapies that may enhance the anti-tumor response. Strategies aimed at reinvigorating T cell activity, alongside targeted therapies addressing specific mutations in cancer cells, may offer new avenues for CCA treatment.
Despite advances in understanding the TME of CCA, significant gaps remain in deciphering the molecular underpinnings that dictate tumor behavior and responses to therapies. Ongoing research into the heterogeneity of the CCA TME and the diverse cellular interactions at play could inform the development of more effective treatment regimens. The incorporation of novel immunotherapeutic strategies, particularly those that target specific immune populations or CAF subtypes, may enhance the response rates in CCA patients.
Given the alarming rise in metabolic dysfunction-associated cholangiocarcinoma cases, there is an urgent need to investigate how the TME adjusts in response to conditions like metabolic syndrome. Understanding the alterations in immune and stromal components in this context is crucial for identifying therapeutic targets that may improve outcomes for patients suffering from this malady.
Collectively, the intricate landscape of the CCA TME, characterized by CAFs, ECM remodeling, and immune cell dynamics, presents a promising yet challenging frontier for cancer research. The shifting balance between pro-tumorigenic and anti-tumorigenic factors within the tumor microenvironment calls for innovative therapeutic strategies that simultaneously disrupt tumor-promoting pathways while enhancing host immune responses. The future of CCA management may hinge on a multi-faceted approach that embraces the complexity of the TME.
Subject of Research: Cholangiocarcinoma (CCA) Tumor Microenvironment
Article Title: Cholangiocarcinoma 2026: status quo, unmet needs and priorities
Article References:
Banales, J.M., Rodrigues, P.M., Affò, S. et al. Cholangiocarcinoma 2026: status quo, unmet needs and priorities.
Nat Rev Gastroenterol Hepatol 23, 65–96 (2026). https://doi.org/10.1038/s41575-025-01153-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41575-025-01153-w
Keywords: Cholangiocarcinoma, tumor microenvironment, cancer-associated fibroblasts, immune cells, extracellular matrix, immunotherapy, ECM remodeling.
