Near-infrared-triggered copper-doped carbon nitride nanocomposite inducing domino effect for synergistic tumor therapy and immune microenvironment reprogramming

Multimodal targeted combination therapies harnessing synergistic interactions have emerged as a transformative paradigm in oncology, gradually superseding conventional monotherapies. We herein report a near-infrared (NIR) light-triggered multifunctional nanocomposite based on copper-doped graphitic-phase carbon nitride (named CNCu@HA), which efficiently eliminates tumors by inducing apoptosis, cuproptosis, and immunogenic cell death (ICD) while initiating robust immune responses. Specifically, the incorporation of copper ions enhances NIR photoabsorption and effectively separates the electron-hole pairs. Moreover, copper ions exhibit Fenton-like reaction capabilities. Consequently, the triggered domino effect of CNCu@HA not only achieves photothermal ablation of tumor cells but also functions as a dual Fenton-like catalyst and photosensitizer, generating excessive reactive oxygen species (ROS) and depleting glutathione (GSH). This process enhances the synergistic efficacy of chemodynamic therapy (CDT) and photodynamic therapy (PDT), promoting tumor cell apoptosis. The resultant intracellular oxidative stress overload impairs mitochondrial function, downregulates ATP levels, and suppresses ATP-dependent heat shock proteins expression, thereby synchronously augmenting the therapeutic effect of mild photothermal therapy (mPTT). Additionally, reduced ATP levels impede copper ion efflux, leading to intracellular copper ions accumulation. Cu²⁺ react with endogenous hydrogen peroxide (H₂O₂) to produce O₂ and Cu⁺, alleviating intratumoral hypoxia and increasing cancer cell susceptibility to cuproptosis. These CNCu@HA-induced cytotoxic effects trigger ICD-driven dendritic cell maturation, M1 macrophage polarization, and CD8⁺ T cell infiltration. This process activates a multilayered cascade of synergistic interactions, potentiating the immune response, reshaping the tumor immune microenvironment, and achieving a domino therapeutic effect, demonstrating remarkable antitumor efficacy in both in vitro and in vivo models.