Interferon-gamma (IFN-γ) has pleiotropic effects on cancer immune checkpoint blockade (ICB), including roles in ICB resistance. We analyzed gene expression in ICB-sensitive versus ICB-resistant tumor cells and identified a strong association between interferon-mediated resistance and expression of Ripk1, a regulator of tumor necrosis factor (TNF) superfamily receptors. Genetic interaction screening revealed that in cancer cells, RIPK1 diverted TNF signaling through NF-κB and away from its role in cell death. This promoted an immunosuppressive chemokine program by cancer cells, enhanced cancer cell survival, and decreased infiltration of T and NK cells expressing TNF superfamily ligands. Deletion of RIPK1 in cancer cells compromised chemokine secretion, decreased ARG1⁺ suppressive myeloid cells linked to ICB failure in mice and humans, and improved ICB response driven by CASP8-killing and dependent on T and NK cells. RIPK1-mediated resistance required its ubiquitin scaffolding but not kinase function. Thus, cancer cells co-opt RIPK1 to promote cell-intrinsic and cell-extrinsic resistance to immunotherapy.

干扰素-γ (IFN-γ) 对癌症免疫检查点阻断 (ICB) 具有多效性作用，包括在 ICB 抗性中的作用。我们分析了 ICB 敏感与 ICB 抗性肿瘤细胞中的基因表达，并确定了干扰素介导的抗性与Ripk1（肿瘤坏死因子 (TNF) 超家族受体的调节因子）的表达之间的强关联。遗传相互作用筛选显示，在癌细胞中，RIPK1 通过 NF-κB 转移 TNF 信号传导，并远离其在细胞死亡中的作用。这促进了癌细胞的免疫抑制趋化因子程序，增强了癌细胞的存活率，并减少了表达 TNF 超家族配体的 T 和 NK 细胞的浸润。癌细胞中 RIPK1 的缺失损害了趋化因子的分泌，降低了 ARG1 ⁺与小鼠和人类 ICB 衰竭相关的抑制性骨髓细胞，以及由 CASP8 杀伤驱动并依赖于 T 和 NK 细胞的 ICB 反应改善。RIPK1 介导的抗性需要其泛素支架而非激酶功能。因此，癌细胞选择 RIPK1 来促进细胞内在和细胞外在对免疫疗法的抵抗。