肿瘤细胞治疗研究
英文原题：Blockade of the CLCF1-CNTFR axis enhances the efficacy of GPC3 CAR-T cell therapy in hepatocellular carcinoma.
肝细胞癌（HCC）具有深度免疫抑制的肿瘤微环境（TME），该微环境限制了免疫检查点阻断和 CAR-T 细胞治疗的疗效。
肝细胞癌（HCC）的免疫抑制性肿瘤微环境（TME）十分显著，限制了免疫检查点阻断和 CAR-T 细胞疗法的效果。本研究发现，心肌营养素样细胞因子因子1（CLCF1）在 HCC 中显著上调，并与预后较差及免疫治疗应答降低相关。据此，我们构建了一种 GPC3 靶向 CAR-T 细胞，可自行分泌可溶性工程化 CNTFR（eCNTFR），在 TME 内局部中和 CLCF1。与常规 GPC3 CAR-T 细胞相比，eCNTFR 装甲型 GPC3 CAR-T 细胞在体外和异种移植模型中具有更强的细胞毒性、更高的细胞因子产生、更好的功能持续性及更优的抗肿瘤疗效。从机制上看，eCNTFR 阻断 CLCF1-CNTFR 轴，抑制 STAT3 信号和 TGF-β 产生，进而抑制肿瘤生长、干性及免疫抑制性 TME 的形成。这些发现确立了 CLCF1 是 HCC 中促进肿瘤生长和免疫抑制的重要介质，并支持 eCNTFR 装甲型 CAR-T 细胞作为 HCC 免疫治疗的有前景策略。
Hepatocellular carcinoma (HCC) exhibits a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immune checkpoint blockade and CAR-T cell therapy. In this study, we identified cardiotrophin-like cytokine factor 1 (CLCF1) as significantly upregulated in HCC and associated with poor prognosis and reduced response to immunotherapy. Accordingly, we engineered a GPC3-targeted CAR-T cell capable of self-secreting a soluble engineered CNTFR (eCNTFR) to locally neutralize CLCF1 within the TME. Compared with conventional GPC3 CAR-T cells, eCNTFR-armored GPC3 CAR-T cells exhibited enhanced cytotoxicity, increased cytokine production, improved functional persistence, and superior antitumor efficacy in vitro and in xenograft models. Mechanistically, eCNTFR-mediated blockade of the CLCF1-CNTFR axis suppressed STAT3 signaling and TGF- production, thereby inhibiting tumor growth, stemness, and the formation of an immunosuppressive TME. These findings establish CLCF1 as a key tumor-promoting and immunosuppressive mediator in HCC and support eCNTFR-armored CAR-T cells as a promising therapeutic strategy for HCC immunotherapy.
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