Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression PMID: 42173096

ADC Targets in Oncology

2026-04-10

Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression

Cell Rep Med. 2026 Jun 16;7(6):102833. doi: 10.1016/j.xcrm.2026.102833.

Jing Hu ¹ , Xiaoman Ju ² , Biping Deng ³ , Kaicheng Tang ² , Dongchen Yuan ² , Xiaofan Sun ² , Lingmei Kong ⁴ , Yixin Xu ⁵ , Zhuo Fu ² , Stephane Koda ² , Simin Shao ² , Yan Chen ² , Guowei Sun ² , Simin Zheng ² , Hongyu Zhao ² , Yaqi Liu ² , Hao Chen ⁶ , Zilong Zong ⁷ , Youzhen Ma ¹ , Huiping Yu ⁸ , Yao Qin ⁸ , Xiaoqing Li ⁸ , Hui Hua ² , Yang Zhao ⁹ , Renxian Tang ² , Kuiyang Zheng ² , Chunrong Tong ¹⁰ , Michele Woei Ling Teng ¹¹ , Xinrui Dong ¹² , Xiaoran Deng ¹² , Yan Li ¹³ , Yan-Long Yang ¹⁴ , Yongqiang Chen ¹⁵ , Juming Yan ¹⁶

Affiliations

1. Department of Bioinformatics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
2. Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
3. Cytology Laboratory, Beijing GoBroad Boren Hospital, Beijing 100070, China.
4. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products; School of Pharmacy, Yunnan University, Kunming, Yunnan 650500, China.
5. Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
6. Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China.
7. School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
8. State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
9. Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
10. Department of Hematology, Beijing GoBroad Boren Hospital, Beijing 100070, China.
11. Department of Anatomical Pathology, National University of Singapore, Singapore 119077, Singapore.
12. School of Anesthesiology, Jiangsu Province Key Laboratory in Anesthesiology and Brain Science, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221009, China.
13. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products; School of Pharmacy, Yunnan University, Kunming, Yunnan 650500, China. Electronic address: [email protected].
14. State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: [email protected].
15. Department of Clinical Laboratory, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China. Electronic address: [email protected].
16. Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: [email protected].

Abstract

Tumor-associated macrophages (TAMs) are key drivers of immunosuppression in the tumor microenvironment, yet effective strategies to reprogram them remain limited. Here, we develop an exogenous precursor-assisted Fungal metabolite (ePAFM) strategy, which generates bioactive Fungal metabolites, and identify IM502, a meroterpenoid-like compound, as a potent TAM modulator. Mechanistically, IM502 primarily inhibits PI3Kγ and redirects STAT signaling from STAT3/6 to STAT1/2 dominance, thereby reversing TAM-mediated immunosuppression, substantially enhancing the abundance and functional quality of natural killer (NK) and T cells. Notably, IM502 reprograms human colorectal Cancer TAMs, restoring CD8⁺ T cell proliferation. It suppresses established tumors and metastases across multiple Cancer types, demonstrating superior efficacy to Other macrophage-targeted agents, effects comparable to clinical drugs, and an ability to overcome PD-1 blockade resistance. This work establishes the ePAFM platform for metabolite generation and highlights the promise of IM502 for Cancer Immunotherapy.

Keywords

PI3Kγ; TAMs; ePAFM; exogenous precursor-assisted fungal metabolites; fungal bioactive metabolite IM502; immune reprogramming; tumor immunotherapy.