A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment.

中文翻译：

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保留 CTLA-4 检查点以实现更安全、更有效的癌症免疫疗法。

癌症免疫疗法的一个主要范例是使用检查点抑制剂来破坏通常保护宿主免受自身免疫性疾病侵害的调节机制。CTLA-4 靶向免疫疗法是帮助建立这种范式的第一个例子。然而，临床测试的抗 CTLA-4 抗体表现出次优功效但毒性高。最近的研究表明，免疫治疗相关的不良事件 (irAE) 和癌症免疫治疗效果 (CITE) 代表了抗 CTLA-4 抗体的不同且治疗上可分离的活性。前者归因于 CTLA-4 检查点的失活，而后者归因于肿瘤微环境中调节性 T 细胞 (Treg) 的选择性耗竭。在这里，我们认为，为了更安全、更有效的 CTLA-4 靶向免疫疗法，