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

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-SO3 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.