Selective Methionine Pool Exhaustion Mediated by a Sequential Positioned MOF Nanotransformer for Intense Cancer Immunotherapy

Abstract Cancer cells are addictive to exogenous methionine to gear toward tumor proliferation. Meanwhile, they can replenish methionine pool from polyamine metabolism through a methionine salvage pathway. However, the current developed therapeutic tactics for methionine depletion are still facing great challenges in terms of the selectivity, safety, and efficiency. Herein, a sequential positioned metal–organic framework (MOF) nanotransformer is designed to selectively exhaust the methionine pool via inhibiting the uptake of methionine and throttling its salvage pathway for enhanced cancer immunotherapy. The MOF nanotransformer can restrain the open source and reduce the reflux of methionine to exhaust the methionine pool of cancer cells. Moreover, the intracellular traffic routes of the sequential positioned MOF nanotransformer match well with the distribution of polyamines, which is conducive to the oxidation of polyamines via its responsive deformability and nanozyme‐augmented Fenton‐like reaction for the final exhaustion of intracellular methionine. These results verify that the well‐designed platform cannot only kill cancer cells efficiently but also promote the infiltration of CD8 and CD4 T cells for intensive cancer immunotherapy. Overall, it is believed that this work will inspire the construction of novel MOF‐based antineoplastic platforms and provide new insights into the development of metabolic‐related immunotherapy.