肿瘤细胞治疗研究
英文原题：Personalized CRISPR knock-in cytokine gene therapy to remodel the tumor microenvironment and enhance CAR T cell therapy in solid tumors.
免疫抑制性肿瘤微环境（TME）仍是实体瘤免疫治疗有效性的核心障碍。
免疫抑制性肿瘤微环境（TME）仍是实体瘤有效免疫治疗的核心障碍。我们提出一种基因治疗策略，可通过肿瘤内在的细胞因子表达实现 TME 的局部重塑。该方法的核心是 CancerPAM，一种多组学生物信息学流程，可识别并排序具有高特异性和整合效率的患者特异性、肿瘤独有 CRISPR-Cas9 敲入位点。以神经母细胞瘤为模型，CancerPAM 对肿瘤测序数据的分析可识别促炎细胞因子（CXCL10、CXCL11、IFNG）的最佳敲入位点，且 CancerPAM 排名与靶位点特异性和敲入效率强相关，验证了其预测性能。CRISPR 介导的 CXCL10 敲入可增强 CAR T 细胞浸润和抗肿瘤疗效（体外和体内），包括人源化 CD34 HuNOG 小鼠；在这些小鼠中，表达 CXCL10 的肿瘤在重建的人免疫微环境中表现出更强的免疫浸润和更持久的肿瘤控制。我们的发现建立了一个安全有效的基于 CRISPR 的细胞因子递送框架，将局部 TME 重塑与细胞免疫疗法相结合，以增强 CAR T 细胞及其他疗法在免疫难治性实体瘤中的效果。
The immunosuppressive tumour microenvironment (TME) remains a central barrier to effective immunotherapy in solid tumours. We present a gene-therapeutic strategy that enables localized remodelling of the TME via tumour-intrinsic cytokine expression. Central to this approach is CancerPAM, a multi-omics bioinformatics pipeline that identifies and ranks patient-specific, tumour-exclusive CRISPR-Cas9 knock-in sites with high specificity and integration efficiency. Using neuroblastoma as a model, CancerPAM analysis of tumour sequencing data identifies optimal knock-in sites for pro-inflammatory cytokines (CXCL10, CXCL11, IFNG), and CancerPAM rankings correlate strongly with target-site specificity and knock-in efficiency, validating its predictive performance. CRISPR-mediated CXCL10 knock-in enhances CAR T cell infiltration and antitumour efficacy in vitro and in vivo, including humanized CD34 HuNOG mice, where CXCL10-expressing tumours show stronger immune infiltration and prolonged tumour control within a reconstituted human immune microenvironment. Our findings establish a framework for safe and effective CRISPR-based cytokine delivery, integrating localized TME remodelling with cellular immunotherapies to enhance CAR T cells and other treatments in immune-refractory solid tumours.
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