Targeting Energy‐Metabolism‐Imbalance Nanoagonist for High‐Resolution NIR‐II Imaging and Potentiated Photoimmunotherapy

ABSTRACT Photoimmunotherapy has emerged as a promising noninvasive strategy for tumor ablation, yet the shallow penetration depth, intrinsic tumor thermotolerance, and immunosuppressive microenvironment fundamentally limit its efficacy. Herein, we developed a targeting energy‐metabolism‐imbalance nanoagonist, CSCN@2‐DG, that integrates precision NIR‐II imaging with synergistic photoimmunotherapy. CSCN, featuring an acceptor–donor–acceptor (A–D–A) structure with a planar π ‐conjugated backbone and branched alkyl chains, confers strong NIR‐I absorption. Upon co‐assembly with 2‐Deoxy‐D‐glucose (2‐DG) into nanoliposomes, CSCN@2‐DG manifests a significant bathochromic shift, characterized by broadened NIR‐II absorption and intense fluorescence emission, enabling deep‐tissue photothermal conversion and high‐resolution imaging with a resolution of 0.32 mm. Mechanistically, NIR‐II irradiation induces mitochondrial dysfunction and DNA damage, while 2‐DG concurrently disrupts glycolysis, depletes adenosine triphosphate (ATP) reserves critical for protein repair, and alleviates lactate‐driven immunosuppression. Transcriptomic analysis confirms that this coordinated attack suppressed cell proliferation‐associated genes while significantly upregulating pro‐inflammatory factors, including Cxcl2 and Ccl2. In vivo, CSCN@2‐DG‐mediated photoimmunotherapy achieved robust tumor ablation, enhanced effector T cell infiltration, reduced regulatory T cells (Tregs), promoted M1 macrophage repolarization, and significantly suppressed pulmonary metastasis. This work provides a simple and effective strategy for constructing NIR‐II photothermal agents, establishing a paradigm for potentiated photoimmunotherapy by glycolytic reprogramming‐mediated energy bankruptcy and metabolic disorder.