A fungi-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1
Wenli Zhao, Yang Zhou, Yuyang Chen, Yicheng Sun, Jiaxin Tang, Yihan Zhu, Jie Ren, Tianxu Du, Handuo Wang, Yuan Gao, Yu Hu, Ling Jiang, Tomohiko Ohwada, Qi Luo, Enguang Bi
Wenli Zhao, Yang Zhou, Yuyang Chen, Yicheng Sun, Jiaxin Tang, Yihan Zhu, Jie Ren, Tianxu Du, Handuo Wang, Yuan Gao, Yu Hu, Ling Jiang, Tomohiko Ohwada, Qi Luo, Enguang Bi
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Research Article Immunology Oncology

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

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.

Authors

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

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Figure 6

SREBP1 is an additional EpA target in Th9 cells.

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SREBP1 is an additional EpA target in Th9 cells. (A) Pathway analysis of...
(A) Pathway analysis of RNA-seq data depicting of lipid metabolism pathways in EpA-treated Th9 cells. (B) Untargeted lipidomics profiling of Th9 cells on day 4 showing global differences in lipid species abundance between control and EpA-treated groups. (C) Predicted binding model of EpA (pink) within SREBP1 (blue). (D and E) CETSA validating EpA–SREBP1 binding. Representative Western blot (D) and quantification (E) of normalized SREBP1 signal intensities across a temperature gradient (°C). (F) Weighted gene coexpression network analysis (WGCNA) of RNA-seq datasets identifying 7 gene modules. (G) Module-trait correlation heatmap revealing a negative association between Il9 and Srebp1-associated gene modules. (H) Validation of inverse correlation between Il9 and Srebf1 expression using RNA-seq data from 12 independent Th9 samples.