Biomimetic Nanoparticles with Dual Targeting for Hepatocellular Carcinoma Promote Tumor Immune System Activation by Enhancing Extracellular ATP Homeostasis

Chemodynamic therapy (CDT) plays a crucial role in transforming the tumor microenvironment by inducing immunogenic cell death (ICD) to eliminate cancer cells. Nonetheless, the effectiveness of CDT in eliciting antitumor immunity is somewhat constrained. The persistent presence of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), in the tumor offsets some of the ICD effects triggered by CDT. Moreover, extracellular adenosine triphosphate (eATP), a crucial damage-related molecular pattern that initiates ICD, is quickly degraded into adenosine, an immunosuppressive metabolite, by CD39 molecules prevalent in the tumor environment, thereby evading immune destruction. In this report, we introduce a nanomaterial, CP@HMM (copper-doped carbon dots and POM1 encapsulated by a hybrid membrane composed of Hepa1–6 and a MDSCs membrane), which targets liver cancer cells and MDSCs and inhibits the ATP–adenosine metabolic pathway. The hybrid membrane, derived from hepatocellular carcinoma (HCC) cells and MDSCs, facilitates the targeted delivery of copper-doped carbon dots (Cu-CDs) to these cells. The potent Fenton-like reactions and the cytotoxicity of copper ions allow CP@HMM to not only kill tumor cells but also eradicate intratumoral MDSCs. Additionally, the CD39 inhibitor POM1 within the system prevents the degradation of eATP induced by the Cu-CDs treatment. This leads to increased eATP levels and drives antitumor immunity activation, including macrophage pyroptosis and dendritic cell maturation, which suppresses primary tumor progression and distant metastases while fostering immune memory to prevent tumor recurrence. Our findings suggest that CP@HMM is an effective drug-delivery system and offers a potential therapeutic alternative for patients with HCC, promising advancements in combined tumor immunotherapy strategies.化学动力学治疗（CDT）通过诱导免疫原性细胞死亡（ICD）以清除癌细胞，在重塑肿瘤微环境中发挥关键作用。然而，CDT诱导抗肿瘤免疫的效果仍存在一定局限。肿瘤中持续存在的免疫抑制细胞（如髓系来源抑制细胞（MDSCs））会抵消CDT诱导产生的部分ICD效应。此外，作为启动ICD的关键损伤相关分子模式，细胞外三磷酸腺苷（eATP）会被肿瘤微环境中广泛存在的CD39分子快速降解为腺苷——一种免疫抑制性代谢物，从而躲避免疫系统的清除。本研究中，我们开发了一种纳米材料CP@HMM：将铜掺杂碳点与POM1包裹于由Hepa1-6细胞膜与髓系来源抑制细胞膜构成的杂合膜中，该纳米材料可靶向肝癌细胞与MDSCs，并抑制ATP-腺苷代谢通路。该杂合膜源自肝细胞癌（HCC）细胞与MDSCs，可助力铜掺杂碳点（Cu-CDs）靶向递送至上述两类细胞。强劲的类芬顿反应与铜离子的细胞毒性，使CP@HMM既能杀伤肿瘤细胞，又能清除肿瘤内的MDSCs。此外，体系中的CD39抑制剂POM1可阻断Cu-CDs处理诱导的eATP降解过程。这一过程可提升eATP水平，进而激活抗肿瘤免疫应答，包括巨噬细胞焦亡与树突状细胞成熟，从而抑制原发肿瘤进展与远处转移，同时建立免疫记忆以防止肿瘤复发。本研究结果表明，CP@HMM是一种高效的药物递送系统，可为肝细胞癌患者提供潜在的治疗选择，有望推动肿瘤联合免疫治疗策略的发展。