Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR‐Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.

中文翻译：

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肿瘤微环境响应性纳米胶囊递送 CRISPR/Cas9 重新编程肝癌中的免疫抑制微环境

癌症免疫疗法已在多种肿瘤中表现出显着疗效，但其治疗肝细胞癌（HCC）的效果仍然有限。因此，迫切需要寻找新的免疫治疗靶点并制定相应的干预策略。生物信息学分析显示，生长分化因子15（GDF15）在HCC中高表达，与HCC患者不良预后密切相关。前期研究表明GDF15可以促进肿瘤微环境中的免疫抑制。因此，通过基因编辑敲除 GDF15 可能会永久逆转抑制性肿瘤免疫微环境。为了将 CRISPR/Cas9 系统专门递送至 HCC，使用了表面涂有 HCC 靶向肽 (SP94) 的纳米胶囊 (SNC)。这些纳米胶囊含有二硫键（SNCSS）在以高水平谷胱甘肽（GSH）为特征的肿瘤微环境中释放其内容物。在体内，SNCSS靶向HCC细胞，对HCC进展发挥显着抑制作用，促进HCC免疫治疗。从机制上看，CyTOF分析显示HCC的免疫微环境发生了有利的变化，具有杀伤功能的免疫细胞增加，具有抑制功能的免疫细胞减少。这些发现凸显了 CRISPR-Cas9 基因编辑系统在调节免疫微环境和提高现有 HCC 免疫治疗方法有效性方面的潜力。