免疫检查点抑制剂（ICIs），如尼伐替尤和伊匹单抗，不仅可以在广泛的人类癌症中引起抗肿瘤反应，而且还会导致严重的免疫相关不良事件（irAEs），包括死亡。一个未能满足的医学需求是，治疗irAEs时不会削弱ICIs的免疫治疗效果。尽管阿巴特塞普（abatacept）已被用于治疗irAEs，但它可能会中和用于癌症治疗的抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）单克隆抗体，从而降低抗CTLA-4免疫治疗的疗效。为避免这种陷阱，我们比较了野生型阿巴特塞普和CTLA-4-Ig的突变体，以了解它们与临床批准的抗CTLA-4抗体的结合能力以及它们对抗CTLA-4和抗PD-1抗体所赋予的免疫治疗和irAEs的影响。在这里，我们报告了尽管阿巴特塞普会中和抗CTLA-4抗体的治疗效果，但结合到B7-1和B7-2而不是临床使用的belatacept等抗CTLA-4抗体的突变体能够消除irAEs，而不影响癌症免疫治疗。我们的数据表明，可以通过提供可溶性CTLA-4变异体来纠正抗CTLA-4引起的irAEs，并且临床可用的belatacept可能成为一种广泛适用的药物，可以消除irAEs而保留CTLA-4靶向ICIs的治疗效果。

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.