Global Cold Local Photothermal‐Mediated Synergistic Metabolic Antitumor Immunity

ABSTRACT Tumor progression is sustained by aberrant metabolic demand and an immunosuppressive microenvironment. However, current therapeutic strategies are largely confined to local interventions and fail to address tumor metabolic adaptability at the systemic level. Herein, we developed a cold–hot integrated therapeutic paradigm that couples systemic metabolic regulation with localized photothermal immunotherapy to enhance antitumor immunity. Donor–acceptor–donor photothermal molecules were engineered and formulated into nanoliposomes with excellent photothermal performance, enabling efficient tumor ablation and induction of immunogenic cell death. Meanwhile, cold exposure activated the systemic metabolic sink function of brown adipose tissue, inducing host–tumor nutrient competition that significantly depleted glucose and glutamine. This suppressed tumor glycolysis, alleviated hypoxia, and downregulated myeloid‐derived suppressor cell infiltration. Importantly, these two processes formed a synergistically amplified positive feedback loop. Photothermal therapy disrupted tumor vasculature, further restricting nutrient supply and reinforcing cold exposure‐induced metabolic inhibition. In turn, systemic metabolic reprogramming sensitized photothermal immunotherapy by remodeling the immunosuppressive tumor microenvironment, ultimately rewiring the tumor metabolism–immunity axis. The synergistic strategy achieved enhanced systemic antitumor immunity, significantly inhibiting both primary and distant tumor growth. This work proposes a remote metabolic regulation framework, providing a new avenue for overcoming metabolic adaptability and immunosuppression in cancer therapy.