The Microbial Metabolite IDA Sensitizes Tumor Cells to ARF1 Inhibition by Inducing SVIL-dependent Senescence.

While pharmacological inhibition of ARF1 exhibits robust antitumor activity, its therapeutic efficacy is constrained by tissue-specific limitations. To augment the clinical potential of our developed ARF1 inhibitor, DU102, we pursued a strategy of senescence induction. A screen for endogenous senescence-inducing metabolites identified trans-3-indoleacrylic acid (IDA), a microbiota-derived metabolite, as a potent senescence inducer. We demonstrate that IDA acts through targeting supervillin (SVIL), leading to subsequent enhancement of the expression of the senescence-associated enzyme galactosidase beta 1 (GLB1). In vivo, IDA enhanced the antitumor efficacy of DU102 through senescence-dependent sensitization, overcoming tissue-restricted resistance and achieving potent tumor suppression. Further analysis revealed that this combination remodels the tumor microenvironment by coordinately regulating tumor-associated macrophages through different predominant mechanisms: IDA predominantly promotes M1-like polarization via TNFα, whereas ARF1 inhibition primarily drives macrophage expansion through CSF2 upregulation. Our work unveils a novel metabolite-regulated senescence pathway and establishes a rational combination therapy that effectively co-opts tumor-associated macrophages (TAMs) for cancer treatment.