T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells¹, is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8⁺ T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs—but not on CD4⁺ or CD8⁺ T cells—promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8⁺ effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1β (IL-1β) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.

T 细胞免疫球蛋白和含粘蛋白分子 3 (TIM-3) 最初被鉴定为在产生干扰素 γ 的 T 细胞上表达的分子¹，正在成为一种重要的免疫检查点分子，目前正在研究 TIM-3 的治疗阻断。多种人类恶性肿瘤。肿瘤微环境中CD8 ⁺ T 细胞上 TIM-3 的表达被认为是 T 细胞功能障碍的主要标志；然而，TIM-3 也在其他几种类型的免疫细胞上表达，这使得使用抗 TIM-3 单克隆抗体阻断后的结果解释变得混乱。在这里，使用 TIM-3 的条件敲除和单细胞 RNA 测序，我们证明了 TIM-3 对树突状细胞 (DC) 的独特重要性，其中 TIM-3 在 DC 上丢失，但在 CD4 + 或 CD8 + 上^却没有^丢失T细胞——促进强大的抗肿瘤免疫力。TIM-3的缺失阻止DC表达调节程序并促进CD8 ⁺效应细胞和干样T细胞的维持。DC 中 TIM-3 的条件性缺失导致活性氧积累增加，从而导致 NLRP3 炎性小体激活。炎症小体激活或下游效应细胞因子白介素-1β (IL-1β) 和 IL-18 的抑制完全消除了 DC 中 TIM-3 缺失所观察到的保护性抗肿瘤免疫。总之，我们的研究结果揭示了 TIM-3 在调节 DC 功能中的重要作用，并强调了 TIM-3 阻断通过调节炎症小体激活来促进抗肿瘤免疫的潜力。