Same organ, divergent immunity: T-cell exhaustion versus stromal exclusion in hepatocellular carcinoma and intrahepatic cholangiocarcinoma
- 1Department of Oncology, The First Affiliated Hospital of Yangtze University
- 2Clinical Molecular Immunology Center, Department of Immunology, School of Medicine, Yangtze University
- 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Yangtze University, The First People’s Hospital of Jingzhou
Abstract
Although hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) arise in the same organ, they occupy distinct immune geographies within a shared barrier network. HCC is relatively enriched for inflamed yet dysfunctional CD8 ⁺ T-cell states, whereas iCCA is more often characterized by stromal- and myeloid-associated immune exclusion; both patterns can occur in either tumor, but differ in their relative predominance. Immune checkpoint blockade has reshaped the treatment landscape in primary liver cancer, but durable benefit remains limited and heterogeneous. Here, we place the T-cell landscape—not checkpoint expression alone—at the center of comparison, focusing on where tumor-reactive cells reside, the states they occupy, and the factors that constrain their reactivation. By integrating clinical and translational evidence across HCC and iCCA, and distinguishing throughout between mechanisms established in human tumors and those extrapolated from experimental models or from other malignancies, we propose that differences in the T-cell landscape help explain divergent therapeutic responses and provide a testable framework for biomarker-guided combination strategies. The key question is therefore not simply whether to release the checkpoint, but what each tumor’s T-cell ecosystem requires for effective reactivation.
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BibTeX
@article{chen2026same,
title = {{Same organ, divergent immunity: T-cell exhaustion versus stromal exclusion in hepatocellular carcinoma and intrahepatic cholangiocarcinoma}},
author = {YanXi Chen and Tao Peng and Hao Nie and Yan Hu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1944650},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1944650/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Same organ, divergent immunity: T-cell exhaustion versus stromal exclusion in hepatocellular carcinoma and intrahepatic cholangiocarcinoma
AU - YanXi Chen
AU - Tao Peng
AU - Hao Nie
AU - Yan Hu
PY - 2026
DA - 2026/10/16
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1944650
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1944650/full
AB - Although hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) arise in the same organ, they occupy distinct immune geographies within a shared barrier network. HCC is relatively enriched for inflamed yet dysfunctional CD8 ⁺ T-cell states, whereas iCCA is more often characterized by stromal- and myeloid-associated immune exclusion; both patterns can occur in either tumor, but differ in their relative predominance. Immune checkpoint blockade has reshaped the treatment landscape in primary liver cancer, but durable benefit remains limited and heterogeneous. Here, we place the T-cell landscape—not checkpoint expression alone—at the center of comparison, focusing on where tumor-reactive cells reside, the states they occupy, and the factors that constrain their reactivation. By integrating clinical and translational evidence across HCC and iCCA, and distinguishing throughout between mechanisms established in human tumors and those extrapolated from experimental models or from other malignancies, we propose that differences in the T-cell landscape help explain divergent therapeutic responses and provide a testable framework for biomarker-guided combination strategies. The key question is therefore not simply whether to release the checkpoint, but what each tumor’s T-cell ecosystem requires for effective reactivation.
SN - 1664-3224
ER -