Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression
Jing Hu, Xiaoman Ju, Biping Deng, Kaicheng Tang, Dongchen Yuan, Xiaofan Sun, Lingmei Kong, Yixin Xu, Zhuo Fu, Stephane Koda, Simin Shao, Yan Chen, Guowei Sun, Simin Zheng, Hongyu Zhao, Yaqi Liu, Hao
Journal：Cell Reports Medicine
IF：14
DOI：10.1016/j.xcrm.2026.102833
PMID：42173096
Published：2026-05-22
research field：肿瘤微环境肿瘤免疫学药理学免疫治疗微生物学信号转导代谢物发现
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.
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