A fungi-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1

Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum-associated endophytic fungi, as a potent enhancer of Th9 cell differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell-dependent tumor control and enhanced the efficacy of human Th9 CAR T cell therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-12-09
DOI
https://doi.org/10.1172/jci196907
Primary Topic
Fungal Biology and Applications
Type
article
Field-Weighted Citation Impact
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article

A fungi-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1

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Journal of Clinical Investigation
Fungal Biology and Applications
article

A fungi-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1

Tomohiko Ohwada, Jiaxin Tang, Enguang Bi, Yicheng Sun, Handuo Wang, Tian Du, Yu‐Wen Hu, Qi Luo, Ling Jiang, Wenli Zhao, Yuyang Chen, Yuan Gao, Jie Ren, Yihan Zhu, Yang Zhou
article en

Abstract

Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum-associated endophytic fungi, as a potent enhancer of Th9 cell differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell-dependent tumor control and enhanced the efficacy of human Th9 CAR T cell therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.

Journal of Clinical InvestigationVol. 136(3)
Guangzhou University of Chinese Medicine (CN), MRC Laboratory of Molecular Biology (GB), Nanfang Hospital (CN), Zhujiang Hospital (CN), TCM-Intigrated Cancer Center of Southern Medical University (CN), Southern Medical University (CN)
Openalex Percentile: Top 57%
Fungal Biology and Applications
DOIOpen Access PDFOpenAlex
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