An enzyme-responsive nanoplatform rewires host-microbe tryptophan metabolism for cancer immunotherapy

Immunotherapy shows great promise against cancer, yet imbalanced tryptophan (Trp) metabolism drives tumor immune tolerance, severely limiting its efficacy. To address this, we advance a synergistic host-microbe metabolism-regulated strategy that concurrently amplifies microbial indole pathway while suppressing the host kynurenine (Kyn) pathway to correct metabolic and immune dysregulation, thereby enhancing antitumor immunity. To produce an oral co-delivery nanoparticle, mesoporous silica nanoparticles are loaded with Trp via ester bonds and coated with agar containing the metabolism inhibitor NLG919 (NLG). This design enables enzyme-responsive release of Trp and NLG in the large intestine, where microbiota and colorectal tumors coexist. Unlike conventional strategies that either block the Kyn pathway or non-selectively activate both pathways, this platform enhances Trp metabolism toward immunostimulatory microbial indole derivatives while suppressing the immunosuppressive Kyn pathway, thereby synergistically enhancing antitumor immunity and achieving potent efficacy with favorable biosafety, offering a promising metabolism-guided paradigm for safe and effective cancer immunotherapy.