Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T_H1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti–PD-1 and anti–CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T_H1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.

免疫疗法正在彻底改变癌症治疗，但通常受到毒性的限制。将不良事件与伴随的抗肿瘤反应区分开来尚不清楚。在这里，在小鼠中使用抗 CD40 治疗作为 T _H模型1-促进免疫治疗，我们发现肝巨噬细胞促进了局部免疫相关的不良事件。从机制上讲，组织驻留的枯否细胞通过感知淋巴细胞衍生的 IFN-γ 并随后产生 IL-12 来介导肝毒性。相反，树突状细胞对毒性是可有可无的，但可以驱动肿瘤控制。IL-12 和 IFN-γ 本身没有毒性，但会引发中性粒细胞反应，从而确定组织损伤的严重程度。我们在小鼠和人类中观察到抗 PD-1 和抗 CTLA-4 免疫疗法后类似炎症通路的激活。_{这些发现表明巨噬细胞和中性粒细胞是促进 T H} 1 的免疫治疗中异常炎症的介质和效应物，表明毒性和抗肿瘤免疫的不同机制。