Mitoxyperilysis-based molecular subtyping identifies SPP1+ macrophages and IL1B as critical mediators of tumor progression and immunotherapy resistance in intrahepatic cholangiocarcinoma
- 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Henan University of Science and Technology
- 2Department of General Surgery & Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
- 3Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy characterized by poor clinical outcomes. Although mitoxyperilysis has recently emerged as a novel form of regulated cell death, the clinical relevance of mitoxyperilysis-related molecular subtypes in ICC remains largely unexplored. This study aimed to elucidate the clinical significance, immune microenvironment features, and potential therapeutic targets of mitoxyperilysis-related molecular subtypes in ICC. Methods Based on the expression profiles of 45 mitoxyperilysis-related genes, ICC patients were classified into two subtypes using consensus clustering, and the robustness of the classification was validated in the independent GSE89749 cohort. Survival analysis, immune microenvironment characterization, single-cell transcriptomic profiling, in vitro/in vivo experiments, and nomogram construction were subsequently performed to investigate the underlying biological mechanisms and therapeutic implications. Results Two robust mitoxyperilysis-related molecular subtypes were identified. Patients in the high-mitoxyperilysis subtype exhibited significantly poorer overall survival (OS), and subtype classification remained an independent predictor of adverse prognosis. The high-mitoxyperilysis subtype was closely associated with lymph node metastasis, elevated CA19-9 levels, and KRAS mutation. Furthermore, this subtype demonstrated pronounced inflammatory activation, an immunosuppressive tumor microenvironment (TME), increased infiltration of neutrophils and M2 macrophages, and elevated expression of immune checkpoint molecules. Single-cell transcriptomic analysis revealed a marked enrichment of SPP1+ macrophages in the high-mitoxyperilysis subtype, with IL1B and CXCL3 identified as key regulatory molecules. IL1B promoted ICC cell invasion and metastasis. Notably, treatment with diacerein, an IL1B inhibitor, synergized with anti-PD-1 immunotherapy to suppress tumor progression and overcome immunotherapy resistance. Conclusions Mitoxyperilysis-related molecular classification provides a clinically relevant framework for prognostic stratification and prediction of immunotherapeutic responsiveness in ICC. SPP1+ macrophages and IL1B represent potential therapeutic targets, providing a promising strategy for precise diagnosis and treatment of ICC.
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BibTeX
@article{wang2026mitoxyperilysisbased,
title = {{Mitoxyperilysis-based molecular subtyping identifies SPP1+ macrophages and IL1B as critical mediators of tumor progression and immunotherapy resistance in intrahepatic cholangiocarcinoma}},
author = {Yafei Wang and Kai Ding and Jiale Niu and Zhi Li and Xiaobo Zhang},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08680-3},
url = {https://doi.org/10.1186/s12967-026-08680-3},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitoxyperilysis-based molecular subtyping identifies SPP1+ macrophages and IL1B as critical mediators of tumor progression and immunotherapy resistance in intrahepatic cholangiocarcinoma
AU - Yafei Wang
AU - Kai Ding
AU - Jiale Niu
AU - Zhi Li
AU - Xiaobo Zhang
PY - 2026
DA - 2026/08/01
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08680-3
UR - https://doi.org/10.1186/s12967-026-08680-3
AB - Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy characterized by poor clinical outcomes. Although mitoxyperilysis has recently emerged as a novel form of regulated cell death, the clinical relevance of mitoxyperilysis-related molecular subtypes in ICC remains largely unexplored. This study aimed to elucidate the clinical significance, immune microenvironment features, and potential therapeutic targets of mitoxyperilysis-related molecular subtypes in ICC. Methods Based on the expression profiles of 45 mitoxyperilysis-related genes, ICC patients were classified into two subtypes using consensus clustering, and the robustness of the classification was validated in the independent GSE89749 cohort. Survival analysis, immune microenvironment characterization, single-cell transcriptomic profiling, in vitro/in vivo experiments, and nomogram construction were subsequently performed to investigate the underlying biological mechanisms and therapeutic implications. Results Two robust mitoxyperilysis-related molecular subtypes were identified. Patients in the high-mitoxyperilysis subtype exhibited significantly poorer overall survival (OS), and subtype classification remained an independent predictor of adverse prognosis. The high-mitoxyperilysis subtype was closely associated with lymph node metastasis, elevated CA19-9 levels, and KRAS mutation. Furthermore, this subtype demonstrated pronounced inflammatory activation, an immunosuppressive tumor microenvironment (TME), increased infiltration of neutrophils and M2 macrophages, and elevated expression of immune checkpoint molecules. Single-cell transcriptomic analysis revealed a marked enrichment of SPP1+ macrophages in the high-mitoxyperilysis subtype, with IL1B and CXCL3 identified as key regulatory molecules. IL1B promoted ICC cell invasion and metastasis. Notably, treatment with diacerein, an IL1B inhibitor, synergized with anti-PD-1 immunotherapy to suppress tumor progression and overcome immunotherapy resistance. Conclusions Mitoxyperilysis-related molecular classification provides a clinically relevant framework for prognostic stratification and prediction of immunotherapeutic responsiveness in ICC. SPP1+ macrophages and IL1B represent potential therapeutic targets, providing a promising strategy for precise diagnosis and treatment of ICC.
SN - 1479-5876
ER -