Redirecting Tryptophan Metabolism Through Host‐Microbial Crosstalk to Enhance Precise Bioorthogonal Chemoimmunotherapy

Bioorthogonal chemistry offers a promising approach for advancing chemoimmunotherapy, yet two critical challenges remain: (1) achieving deep tumor penetration of catalysts while ensuring precise tumor-confined prodrug activation, and (2) reversing metabolic immunosuppression to potentiate immunotherapy efficacy. To tackle these issues, here we fabricate a bioorthogonal probiotic nanosystem (NP@ZIF-8@Apt-Lr) by engineering prodrug catalysts and an indoleamine 2,3-dioxygenase (IDO) inhibitor onto AS1411 aptamer-modified Lactobacillus reuteri (Lr). AS1411-guided recognition and GSH-responsive prodrug decaging provide a double guarantee for tumor-selective drug activation, enabling localized tumor killing and further immunogenic cell death (ICD). Also, the inherent tumor-homing properties of Lr endow the nanosystem with the ability of penetrating deep tissue. More crucially, the released IDO inhibitor blocks the immunosuppressive kynurenine pathway of tryptophan metabolism, while Lr redirects tryptophan metabolism toward the immunostimulatory indole-3-aldehyde pathway through host-microbial crosstalk. Upon treatment, NP@ZIF-8@Apt-Lr overcomes immune tolerance and stimulates T lymphocyte infiltration into tumors. Furthermore, it significantly enhances the efficacy of chemoimmunotherapy by suppressing bilateral tumor development and inducing an immune memory response. This work presents a new strategy for enhancing bioorthogonal chemoimmunotherapy through precise prodrug activation and probiotic-mediated metabolic reprogramming by host-microbial crosstalk.