Second Near‐Infrared Light‐Activatable Polymeric Nanoantagonist for Photothermal Immunometabolic Cancer Therapy

Abstract Immunometabolic modulation offers new opportunities to treat cancers as it is highly associated with cancer progression and immunosuppressive microenvironment. However, traditional regimens using nonselective small‐molecule immunomodulators lead to the off‐target adverse effects and insufficient therapeutic outcomes. Herein a second near‐infrared (NIR‐II) photothermally activatable semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic therapy of cancer is reported. ASPA backbone is obtained by conjugating vipadenant, an antagonist to adenosine A2A receptor, onto NIR‐II light‐absorbing semiconducting polymer via an azo‐based thermolabile linker. Under deep‐penetrating NIR‐II photoirradiation, ASPA induces tumor thermal ablation and subsequently immunogenic cell death, triggers the cleavage of thermolabile linker, and releases the antagonist to block the immunosuppressive adenosinergic pathway. Such a remotely controlled immunometabolic regulation potentiates cytotoxic T cell functions while suppresses regulatory T cell activities, leading to efficient primary tumor inhibition, pulmonary metastasis prevention, and long‐term immunological memory. Thereby, this work provides a generic polymeric approach for precise spatiotemporal regulation of cancer immunometabolism.