Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis
Abstract
Immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis) is a rare but frequently fatal immune-related adverse event. A comprehensive understanding of the cellular and molecular determinants driving ICI-myocarditis is essential for improving diagnostic precision and developing targeted interventions. We delineate the immune landscape of ICI-myocarditis via scRNA-seq, flow cytometry, Olink proteomics, and multiplex cytokine profiling. We demonstrate that high levels of baseline ISG15⁺CD8⁺ T cells are linked to the proinflammatory features of monocytes and in vitro experiments confirm the existence of circulating ISG15⁺CD8⁺ T cells with a high potential to induce cardiomyocyte apoptosis, supporting their pathogenic potential for cardiomyocyte cytotoxicity. Notably, intercellular crosstalk between these subsets is possibly mediated via the CCL2-CCR2 axis, and its blockade attenuated ICI-induced cardiac injury in vivo. Based on the inflammatory signature in ICI-myocarditis, we develop an 8-protein custom panel with promising performance in distinguishing ICI-myocarditis from other ICIs-treated controls. JAK-STAT pathway activation promotes inflammatory programs in both ISG15⁺CD8⁺ T cells and monocytes. Furthermore, JAK-STAT inhibition ameliorates cardiac dysfunction and inflammatory infiltration while enhancing the response to anti-PD-1 therapy in mouse models. In summary, this study implicates immune-pathogenic features of ICI-myocarditis and provides a possible basis for future therapies.
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BibTeX
@article{zhang2026integrated,
title = {{Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis}},
author = {Shi-Long Zhang and Qing-Qing Cai and Jian Zhang and Yuan Liu and Hao Lu and Ye-Rui Zhang and Yu-Chen Xu and Hai-Xiang Peng and Hui-Yong Chen and Yan Wang and Lei-Lei Cheng and Jun-Bo Ge},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77262-0},
url = {https://www.nature.com/articles/s41467-026-77262-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis
AU - Shi-Long Zhang
AU - Qing-Qing Cai
AU - Jian Zhang
AU - Yuan Liu
AU - Hao Lu
AU - Ye-Rui Zhang
AU - Yu-Chen Xu
AU - Hai-Xiang Peng
AU - Hui-Yong Chen
AU - Yan Wang
AU - Lei-Lei Cheng
AU - Jun-Bo Ge
PY - 2026
DA - 2026/10/14
JO - Nature Communications
DO - 10.1038/s41467-026-77262-0
UR - https://www.nature.com/articles/s41467-026-77262-0
AB - Immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis) is a rare but frequently fatal immune-related adverse event. A comprehensive understanding of the cellular and molecular determinants driving ICI-myocarditis is essential for improving diagnostic precision and developing targeted interventions. We delineate the immune landscape of ICI-myocarditis via scRNA-seq, flow cytometry, Olink proteomics, and multiplex cytokine profiling. We demonstrate that high levels of baseline ISG15⁺CD8⁺ T cells are linked to the proinflammatory features of monocytes and in vitro experiments confirm the existence of circulating ISG15⁺CD8⁺ T cells with a high potential to induce cardiomyocyte apoptosis, supporting their pathogenic potential for cardiomyocyte cytotoxicity. Notably, intercellular crosstalk between these subsets is possibly mediated via the CCL2-CCR2 axis, and its blockade attenuated ICI-induced cardiac injury in vivo. Based on the inflammatory signature in ICI-myocarditis, we develop an 8-protein custom panel with promising performance in distinguishing ICI-myocarditis from other ICIs-treated controls. JAK-STAT pathway activation promotes inflammatory programs in both ISG15⁺CD8⁺ T cells and monocytes. Furthermore, JAK-STAT inhibition ameliorates cardiac dysfunction and inflammatory infiltration while enhancing the response to anti-PD-1 therapy in mouse models. In summary, this study implicates immune-pathogenic features of ICI-myocarditis and provides a possible basis for future therapies.
SN - 2041-1723
ER -