Conventional type 1 dendritic cells (cDC1s) are critical for antitumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8⁺ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the antitumor functions of cDC1s in immunogenic tumors are poorly understood. Using single-cell transcriptomics to examine the molecular pathways regulating intratumoral cDC1 maturation, we found nuclear factor κB (NF-κB) and interferon (IFN) pathways to be highly enriched in a subset of functionally mature cDC1s. We identified an NF-κB–dependent and IFN-γ–regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. By mapping the trajectory of intratumoral cDC1 maturation, we demonstrated the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IFN regulatory factor 1 (IRF1) in cDC1s, resulting in impaired expression of IFN-γ–responsive genes and consequently a failure to efficiently recruit and activate antitumoral CD8⁺ T cells. Last, we demonstrate the relevance of these findings to patients with melanoma, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development of new diagnostic and therapeutic approaches to improve cancer immunotherapy.

传统的 1 型树突状细胞 (cDC1s) 对抗肿瘤免疫至关重要。它们从垂死的肿瘤细胞中获取抗原并将它们交叉呈递给 CD8 ⁺T 细胞，促进肿瘤特异性细胞毒性 T 细胞的扩增。然而，在免疫原性肿瘤中控制 cDC1s 抗肿瘤功能的信号通路知之甚少。使用单细胞转录组学检查调节肿瘤内 cDC1 成熟的分子途径，我们发现核因子 κB (NF-κB) 和干扰素 (IFN) 途径在功能成熟的 cDC1 子集中高度富集。我们在 cDC1s 中鉴定了一个 NF-κB 依赖性和 IFN-γ 调节的基因网络，包括专门用于募集和激活细胞毒性 T 细胞的细胞因子和趋化因子。通过绘制肿瘤内 cDC1 成熟的轨迹，我们证明了 NF-κB 和 IFN 信号通路对肿瘤浸润 cDC1 的动态重编程。⁺ T 细胞。最后，我们证明了这些发现与黑色素瘤患者的相关性，表明与 cDC1s 相关的 NF-κB/IRF1 轴的激活与改善的临床结果有关。因此，cDC1s 中的 NF-κB/IRF1 轴可能代表开发新的诊断和治疗方法以改善癌症免疫治疗的重要焦点。