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].
PMID: 42173096 DOI: 10.1016/j.xcrm.2026.102833
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.
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