Zhang Xiaoqian, Qiu Guanhua, Chen Yuanyuan, Wang Sida, Han Chuangye, Mo Shutian, Liu Junjie, Wang Duo, Zeng Zisan
Department of Radiology, Department of Ultrasound, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, China.
Department of Radiology, Department of Ultrasound, Guangxi Medical University Cancer Hospital, Guangxi Medical University, No. 71 Hedi Road, Nanning, 530021, China.
Mater Today Bio. 2025 Jul 25;34:102132. doi: 10.1016/j.mtbio.2025.102132. eCollection 2025 Oct.
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. Cu react with endogenous hydrogen peroxide (HO) to produce O 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 and models.
利用协同相互作用的多模态靶向联合疗法已成为肿瘤学中一种变革性的模式,逐渐取代传统的单一疗法。我们在此报告一种基于铜掺杂石墨相氮化碳的近红外(NIR)光触发多功能纳米复合材料(命名为CNCu@HA),它通过诱导细胞凋亡、铜死亡和免疫原性细胞死亡(ICD)同时引发强大的免疫反应来有效消除肿瘤。具体而言,铜离子的掺入增强了近红外光吸收并有效分离电子 - 空穴对。此外,铜离子具有类芬顿反应能力。因此,CNCu@HA触发的多米诺效应不仅实现了肿瘤细胞的光热消融,还作为双功能类芬顿催化剂和光敏剂,产生过量的活性氧(ROS)并消耗谷胱甘肽(GSH)。这一过程增强了化学动力疗法(CDT)和光动力疗法(PDT)的协同疗效,促进肿瘤细胞凋亡。由此产生的细胞内氧化应激过载损害线粒体功能,下调ATP水平,并抑制ATP依赖性热休克蛋白表达,从而同步增强温和光热疗法(mPTT)的治疗效果。此外,降低的ATP水平阻碍铜离子外流,导致细胞内铜离子积累。铜与内源性过氧化氢(HO)反应生成O和Cu,减轻肿瘤内缺氧并增加癌细胞对铜死亡的敏感性。这些CNCu@HA诱导的细胞毒性作用触发ICD驱动的树突状细胞成熟、M1巨噬细胞极化和CD8 T细胞浸润。这一过程激活了多层协同相互作用的级联反应,增强免疫反应,重塑肿瘤免疫微环境,并实现多米诺治疗效果,在 和 模型中均显示出显著的抗肿瘤疗效。
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