Dual Metabolic Inhibition Via Vanadium–NO Synergistic Nanoplatform Potentiates Cancer Immunotherapy

ABSTRACT Immunotherapy has emerged as a pivotal strategy in cancer treatment. However, tumor metabolic reprogramming not only promotes cancer cell survival but also fosters an immunosuppressive tumor microenvironment (TME), thereby hindering immune activation. To address these challenges, we developed a novel multifunctional hybrid nanoplatform, termed VTLM, via microfluidics‐assisted self‐assembly of bioactive vanadium species and an arginine‐based nitric oxide (NO) donor. This nanoplatform synergistically modulates tumor metabolism to potentiate antitumor immunity. Specifically, we observed that vanadium species in VTLM reduce pyruvate kinase M2 (PKM2) expression and enzymatic activity, which may contribute to the suppression of tumor glycolysis, while tumor cell‐targeted NO release induces mitochondrial damage, ultimately enforcing a dual metabolic blockade. This strategy overcomes the metabolic plasticity of tumor cells, a major obstacle in single‐pathway metabolic targeting. Importantly, VTLM‐induced metabolic collapse not only drives lactate depletion within the TME but also promotes immunogenic cell death, thereby reversing immunosuppression and amplifying antitumor responses. Furthermore, VTLM exhibited marked therapeutic efficacy in a 4T1 subcutaneous tumor model, achieving an 80.7% tumor weight‐based inhibition rate alongside robust intratumoral immune activation. Collectively, this study establishes a nanoplatform centered on multi‐metabolic regulation, which may hold potential for further preclinical evaluation as a strategy to enhance cancer immunotherapy.