基于真菌代谢物的免疫疗法克服了肿瘤相关的巨噬细胞免疫抑制
Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression.
摘要(中文译文)
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境中免疫抑制的关键驱动因素，然而对其进行重编程的有效策略仍然有限。在此，我们开发了一种外源性前体辅助真菌代谢物（ePAFM）策略，该策略可生成具有生物活性的真菌代谢物，并鉴定出IM502——一种类梅罗萜化合物——作为一种强效的TAM调节剂。在机制上，IM502主要抑制PI3Kγ，并将STAT信号从STAT3/6主导转向STAT1/2主导，从而逆转TAM介导的免疫抑制，大幅提升自然杀伤（NK）细胞和T细胞的丰度及功能质量。值得注意的是，IM502可重编程人结直肠癌TAMs，恢复CD8 T细胞增殖。它在多种癌症类型中抑制已形成的肿瘤和转移灶，展现出优于其他巨噬细胞靶向药物的疗效、与临床药物相当的效应，以及克服PD-1阻断耐药的能力。本研究建立了用于代谢物生成的ePAFM平台，并凸显了IM502在癌症免疫治疗中的前景。
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.
如何引用
AMA
Jing Hu, Xiaoman Ju, Biping Deng, Kaicheng Tang, Dongchen Yuan, Xiaofan Sun, et al. Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression.. Cell reports. Medicine. 2026; doi:10.1016/j.xcrm.2026.102833.
APA
Jing Hu, Xiaoman Ju, Biping Deng, Kaicheng Tang, Dongchen Yuan, Xiaofan Sun, et al (2026). Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression.. Cell reports. Medicine. https://doi.org/10.1016/j.xcrm.2026.102833
GB/T 7714
Jing Hu, Xiaoman Ju, Biping Deng, Kaicheng Tang, Dongchen Yuan, Xiaofan Sun, et al. Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression.[J]. Cell reports. Medicine, 2026 doi:10.1016/j.xcrm.2026.102833.
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