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To tackle these issues, here we fabricate a bioorthogonal probiotic nanosystem (NP@ZIF\u20108@Apt\u2010Lr) by engineering prodrug catalysts and an indoleamine 2,3\u2010dioxygenase (IDO) inhibitor onto AS1411 aptamer\u2010modified Lactobacillus reuteri (Lr). AS1411\u2010guided recognition and GSH\u2010responsive prodrug decaging provide a double guarantee for tumor\u2010selective drug activation, enabling localized tumor killing and further immunogenic cell death (ICD). Also, the inherent tumor\u2010homing 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\u20103\u2010aldehyde pathway through host\u2010microbial crosstalk. Upon treatment, NP@ZIF\u20108@Apt\u2010Lr 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\u2010mediated metabolic reprogramming by host\u2010microbial crosstalk.<\/jats:p>","DOI":"10.1002\/adma.202517934","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T06:38:30Z","timestamp":1766817510000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Redirecting Tryptophan Metabolism Through Host\u2010Microbial Crosstalk to Enhance Precise Bioorthogonal Chemoimmunotherapy"],"prefix":"10.1002","volume":"38","author":[{"given":"Yue","family":"Sun","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry, Chinese Academy of Sciences  Changchun Jilin P. R. 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