NIR‐II Small‐Molecule Shuttle‐Like Nanoassemblies for Mild‐Temperature NIR‐II Photothermal Enhanced Cuproptosis/STING Activation and Cancer Immunotherapy

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ABSTRACT The risk of tumor recurrence and insufficient immune responses are formidable challenges for cancer therapy based on mild‐temperature second near‐infrared region (NIR‐II) photothermal therapy (PTT). Herein, we report a multifunctional NIR‐II phototheranostic agent (Cu‐P/MTO@BTS) that integrates shuttle‐like NIR‐II small‐molecule nanoassemblies with copper clusters (Cu‐P) and the STING agonist mitoxantrone (MTO), enabling tumor immunotherapy via synergistic mild‐temperature NIR‐II PTT‐enhanced cuproptosis and STING activation. The shuttle‐like nanoassemblies of BCT‐SO 3 were found to be effective as NIR‐II photothermal agents, achieving an impressive photothermal conversion efficiency of 63.46% upon irradiation with a laser of 1064 nm wavelength. The NIR‐II PTT‐responsive release of Cu‐P from Cu‐P/MTO@BTS induced cuproptosis, ·OH generation, mitochondrial dysfunction, and mitochondrial DNA (mtDNA) release into the cytosol of cancer cells. Moreover, the MTO released from Cu‐P/MTO@BTS caused nuclear DNA damage and synergized with the cytosolic mtDNA (released via the activity of Cu‐P) to enhance STING activation. Notably, the synergistic mild‐temperature NIR‐II PTT‐enhanced cuproptosis and STING activation were found to promote immunogenic cell death (ICD), facilitate dendritic cell maturation, augment T‐cell infiltration, and reverse the immunosuppressive tumor microenvironment. To summarize, the Cu‐P/MTO@BTS nanoplatform developed herein exhibits robust antitumor therapeutic efficacy under both in vitro and in vivo conditions.

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