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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\u2010assisted self\u2010assembly of bioactive vanadium species and an arginine\u2010based 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\u2010targeted 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\u2010pathway metabolic targeting. Importantly, VTLM\u2010induced 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\u2010based inhibition rate alongside robust intratumoral immune activation. Collectively, this study establishes a nanoplatform centered on multi\u2010metabolic regulation, which may hold potential for further preclinical evaluation as a strategy to enhance cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/smll.76361","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T19:32:21Z","timestamp":1792351941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Metabolic Inhibition Via Vanadium\u2013NO Synergistic Nanoplatform Potentiates Cancer Immunotherapy"],"prefix":"10.1002","author":[{"given":"Ruizhi","family":"Tian","sequence":"first","affiliation":[{"name":"State Key Laboratory of High Performance Ceramics Shanghai Institute of Ceramics Chinese Academy of Sciences  Shanghai P. R. China"},{"name":"Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of Sciences  Beijing P. R. 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