Immunogenomic Insights Transform Understanding of Cholangiocarcinoma
Researchers from the University of Copenhagen recently conducted a comprehensive review highlighting how immunogenomics is reshaping the understanding of cholangiocarcinoma (CCA).
In the journal Hepatology the investigators discuss the ways in which immune dysfunction and genomic alterations interplay to drive tumor initiation, progression, and therapeutic response.
Study Findings: Genomics and Immune Dysregulation
The authors reviewed thousands of primary CCA tumors, identifying distinct immunogenomic profiles between intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. iCCA commonly harbors IDH1/2 mutations, FGFR2 fusions, and ARID1A alterations, while eCCA more often presents with KRAS, TP53, and SMAD4 mutations. These differences influence immune cell composition, tumor microenvironment, and clinical outcomes.
The review underscores that tumor behavior arises not from single mutations but from coalteration spectra interacting with immune pathways. Dysfunction in the cancer-immunity cycle—such as impaired antigen presentation, T cell exhaustion, and expansion of regulatory T cells—permits tumor escape and metastasis. Genomic instability and high tumor mutational burden (TMB) were linked with variable immune activity, creating opportunities for patient stratification.
“Integrative immunogenomic analyses provide a biological rationale for immune-based patient stratification,” the authors wrote. However, they caution that distinguishing tumor-promoting immune signals from incidental “bystander” effects remains challenging.
Clinical Implications: Toward Precision Immunotherapy
These findings reinforce the need to move beyond anatomic or single-gene classification toward immune-genomic stratification. Such an approach could optimize patient selection for immune checkpoint inhibitors (PD-1/PD-L1), STING agonists, or other immunomodulatory therapies. The review also highlights the emerging role of biomarkers such as microsatellite instability (MSI-H), DNA mismatch repair deficiency (dMMR), and neoantigen burden (TNB) in predicting immunotherapy response.
For clinicians, tailoring therapy to both genomic alterations and immune functionality may improve outcomes in a cancer with otherwise poor prognosis. The authors emphasize the promise of combining targeted agents (FGFR or IDH inhibitors) with immunotherapies to overcome immune evasion mechanisms.
Expert Commentary
“Cholangiocarcinoma is not one disease but many, shaped by both the genome and the immune system,” the investigators wrote. “Functionally uncoupling tumor-promoting from tumor-suppressing immune mechanisms will be critical for developing effective immunotherapies and identifying biomarkers to guide treatment.”
By integrating genomic and immunologic perspectives, this review provides a framework for precision immuno-oncology in cholangiocarcinoma. Future research must validate immune-based biomarkers and develop strategies that exploit tumor–immune vulnerabilities, offering hope for improved survival in this challenging malignancy.
Reference:
Gehl V, O’Rourke CJ, Andersen JB. Immunogenomics of cholangiocarcinoma. Hepatology. 2025; 82(2):522-539 DOI: 10.1097/HEP.0000000000000688
