Abstract

Despite the promising potential of immunotherapy in oncology, its efficacy is often limited by tumor metabolic reprogramming‐driven immunosuppressive microenvironment. Specifically, the reprogramming of amino acid metabolism, such as glutamine metabolism and tryptophan metabolism, not only sustains tumor growth but also facilitates immune evasion. Herein, we engineered CMZD NPs, a ZIF‐8‐based nanoparticle co‐delivering a glutaminase inhibitor (CB‐839) and a tryptophan metabolism inhibitor (1‐MT) to synergistically disrupt tumor immunosuppression through metabolic reprogramming. This nanoparticle system effectively blocks the glutamine metabolic pathway, amplifies oxidative stress, induces mitochondrial dysfunction, and ultimately leads to tumor cell death. Furthermore, it triggers the immunogenic cell death (ICD) and activates the cGAS‐STING pathway. Simultaneous inhibition of tryptophan‐to‐kynurenine conversion reduced kynurenine accumulation and altered glutamine metabolism, thereby reversing the tumor immunosuppressive microenvironment. The enhanced ICD effect generates new antigens that promote dendritic cell maturation, thereby recruiting and activating cytotoxic T lymphocytes. Ultimately, this nanoparticulate immune therapy enhancer inhibits both primary and distant tumors. This dual amino acid metabolism‐targeting strategy holds promise for enhancing tumor immunogenicity and alleviating tumor‐induced immune suppression, thereby improving the efficacy of immunotherapy.