大肠杆菌CNF1模拟层粘连蛋白的结构基础及其在肿瘤免疫治疗中的潜在应用
Structural basis of laminin mimicry by E. coli CNF1 and its therapeutic potential for cancer immunotherapy
摘要
该研究利用冷冻电镜解析了全长CNF1毒素、CNF1–BCAM复合物以及生理性层粘连蛋白511–BCAM复合物的高分辨率结构，发现CNF1靶向BCAM的V2结构域，模拟层粘连蛋白511的结合模式，且亲和力更高，可竞争性置换细胞表面的生理配体。基于此，作者构建了以CNF1 D5片段为基础的T细胞衔接器（TCE），在体外可有效引导T细胞杀伤BCAM高表达肿瘤细胞，并在雌性小鼠转移性卵巢癌模型中抑制肿瘤进展。研究提示病原体来源的高亲和相互作用可被改造用于BCAM阳性肿瘤的免疫治疗，但原文未涉及生殖或胚胎生物学功能。
原文摘要
The E. coli CNF1 toxin hijacks the host laminin 511 receptor, Lu/BCAM, to enter cells. Here, we present the high-resolution cryo-EM structures of full-length CNF1, the CNF1-BCAM complex, and the physiological laminin 511-BCAM complex. Structural analysis uncovers that CNF1 targets the V2 domain of BCAM, mimicking the interaction mode of laminin 511. We demonstrate that CNF1 binds BCAM with higher affinity than laminin 511, effectively displacing the physiological ligand from the cell surface. Leveraging this high-affinity interaction, we engineered a CNF1 D5-based T-cell engager (TCE). This TCE potently directs T cells to kill BCAM-overexpressing tumor cells in vitro and suppresses tumor progression in a metastatic ovarian cancer mouse model in female mice. These findings provide structural insight into how CNF1 hijacks the BCAM receptor and show how a pathogen-derived, high-affinity interaction can be harnessed to redirect T cells against BCAM-expressing tumors.
推荐理由：冷冻电镜结构与功能验证扎实，并实现了从结构到T细胞衔接器治疗的转化，但其核心是细菌毒素-受体互作与卵巢癌免疫治疗，与生殖医学、配子胚胎生物学基本无直接关联，仅对关注卵巢肿瘤免疫微环境者有一定参考价值。
文献解读
尚未生成。