Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.

第 3 组先天淋巴细胞 (ILC3) 调节免疫和炎症，但它们在癌症中的作用仍然难以捉摸。在这里，我们发现结直肠癌 (CRC) 表现为 ILC3 改变，其特点是频率降低、可塑性增加以及 T 细胞失衡。我们评估了小鼠中这些变化的后果，并确定 ILC3 和 T 细胞之间通过主要组织相容性复合物 II 类 (MHCII) 进行对话对于支持微生物群的定植是必要的，从而随后在肠道和肿瘤微环境中诱导 1 型免疫。因此，缺乏 ILC3 特异性 MHCII 的小鼠会出现侵袭性 CRC，并对抗 PD-1 免疫疗法产生耐药性。最后，肠道 ILC3 失调的人类体内的微生物群在转移到小鼠体内时无法诱导 1 型免疫和免疫治疗反应。总的来说，这些数据定义了 ILC3 在癌症中的保护作用，并表明它们对 CRC 的固有破坏会导致适应性免疫功能失调、肿瘤进展和免疫治疗耐药。