What question did this study set out to answer?

The aim is to explore the complex tumor microenvironment of cholangiocarcinoma and its implications for therapy.

August 6, 2026Journal of Translational Medicine0 citationsOpen Access

Decoding the cholangiocarcinoma tumor microenvironment: from single-cell and spatial atlases to translational therapeutic targeting

LZLonghao Zhang KZKai Zhang JXJingnan Xue

Key Points

The aim is to explore the complex tumor microenvironment of cholangiocarcinoma and its implications for therapy.
Analysis of recent advances in single-cell RNA sequencing, spatial transcriptomics, and multiplex imaging
Identification of cellular states and spatial niches within the tumor microenvironment
Examination of communication axes linking cellular heterogeneity to therapy resistance.
Characterization of cellular states such as CD146 + vascular cancer-associated fibroblasts and SPP1 + macrophages
Identification of major communication pathways like IL-6/IL-6R and TGF-β/TGFBR associated with immune escape
Proposed translational framework to guide future patient stratification and combination therapies.

Abstract

Cholangiocarcinoma is a heterogeneous biliary malignancy characterized by late diagnosis, stromal desmoplasia, immune exclusion, and frequent resistance to chemotherapy, immunotherapy, and molecularly targeted therapy. Although genomic stratification has enabled biomarker-directed treatment for selected patients, cancer cell-intrinsic alterations alone do not fully explain disease progression or therapeutic failure. Recent advances in single-cell RNA sequencing, single-cell multi-omics, spatial transcriptomics, spatial proteomics, multiplex imaging, and pathomics have redefined the CCA tumor microenvironment as an active ecosystem composed of malignant cholangiocytes, cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, exhausted CD8 + T cells, natural killer cells, B cells/plasma cells, endothelial cells, extracellular matrix, and tertiary lymphoid structures. These approaches have identified clinically relevant cellular states and spatial niches, including CD146 + vascular cancer-associated fibroblasts, LGALS1 + fibroblasts, SPP1 + macrophages, MEOX1 + regulatory T cells, POSTN+ fibroblast-rich invasive fronts, and CAF-TAM-vascular interaction units. Major communication axes such as IL-6/IL-6R, TGF-β/TGFBR, SPP1/CD44, CXCL12/CXCR4, PD-1/PD-L1, VEGF/VEGFR, and POSTN/integrins connect cellular heterogeneity with immune escape, invasion, angiogenesis, and therapy resistance. This review synthesizes current single-cell and spatial atlases of CCA and proposes a conceptual translational framework in which TME-derived cellular states, spatial biomarkers, and druggable communication axes may inform patient stratification and rational combination therapy. Because many proposed TME phenotypes and composite biomarkers remain atlas-derived, correlative, or preclinical, this framework should be viewed as a roadmap for prospective validation rather than as a clinically established classification.

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