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.