加州大学Michael Demetriou课题组取得一项新突破。他们开发出通过维可牢样密度依赖靶向肿瘤相关碳水化合物抗原的安全免疫抑制耐药泛癌症免疫治疗。相关论文发表在2025年9月25日出版的《细胞》杂志上。
研究人员描述了甘聚糖依赖性T细胞招募者（GlyTR）泛癌症免疫疗法，它利用高亲和力的“维可牢样”凝集素结合来杀死高但不低表达TACA的细胞。GlyTR1和GlyTR2分别结合免疫抑制β1,6GlcNAc支链Nn-聚糖或多种TACAs (Tn, sialyl-Tn, LacDiNAc和GD2)，克服肿瘤微环境中的免疫抑制机制，触发靶密度依赖性T细胞介导的泛癌杀伤，但它们在具有类似人的TACA表达的小鼠中缺乏毒性。与TACAs结合的密度依赖性凝集素提供了高效和安全的泛癌症免疫治疗方法。
研究人员表示，双特异性抗体和嵌合抗原受体T细胞是临床主题中最有效的癌症免疫治疗方法之一，但大多数癌症的靶向性仍然很差。高亲和力抗体需要最大限度地杀死检测正常组织中的低抗原表达，冒着“靶向，非癌症”毒性。这迫使鉴定癌症限制性细胞表面蛋白抗原，这是罕见的。肿瘤相关碳水化合物抗原（TACAs）是已知的最丰富和最广泛的癌症抗原，但抗体的靶向性很差。
附：英文原文
Title: Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens
Author: Raymond W. Zhou, Paresh Kumar Purohit, Jai Hyun Kim, Sung-Uk Lee, Nicole Burshteyn, Delia Tifrea, Andres Cordon, Ani Grigorian, Barbara L. Newton, Robert A. Edwards, Michael Demetriou
Issue&Volume: 2025-09-25
Abstract: Bispecific antibodies and chimeric antigen receptor T cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking “on-target, off-cancer” toxicity. This compels identification of cancer-restricted cell-surface protein antigens, which are rare. Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. Here, we describe glycan-dependent T cell recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity “velcro-like” lectin binding to kill cells with high but not low TACA expression. GlyTR1 and GlyTR2 bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs (Tn, sialyl-Tn, LacDiNAc, and GD2), respectively, overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
DOI: 10.1016/j.cell.2025.09.001
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01032-3