I型干扰素因其在肿瘤免疫治疗过程中各种类型免疫细胞中的作用而得到广泛认可。然而，它们对肿瘤细胞的直接影响尚不清楚。氧化磷酸化通常潜伏在肿瘤细胞中。氧化磷酸化是否可以作为免疫治疗的目标尚不清楚。在这里，我们发现肿瘤细胞对 I 型干扰素（而非 II 型干扰素）的反应对于雌性小鼠的 CD47-SIRPα 阻断免疫治疗至关重要。从机制上讲，I 型干扰素通过以 ISG15 依赖性方式激活氧化磷酸化以产生 ATP，从而直接重新编程肿瘤细胞代谢。由于分泌性自噬增强，I 型干扰素也促进 ATP 细胞外释放。从功能上讲，氧化磷酸化或自噬遗传缺陷的肿瘤细胞对 CD47-SIRPα 阻断具有抵抗力。 CD47-SIRPα 阻断后释放的 ATP 是通过 P2X7 受体介导的树突状细胞激活诱导抗肿瘤 T 细胞反应所必需的。基于这一机制，设计了与 ATP 降解胞外酶抑制剂 CD39 和 CD73 的组合，并显示出与 CD47-SIRPα 阻断的协同抗肿瘤作用。总之，这些数据揭示了 I 型干扰素对肿瘤免疫治疗的肿瘤细胞代谢重编程的重要作用，并提供了利用该机制增强 CD47-SIRPα 阻断功效的合理策略。© 2024。作者。

Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.© 2024. The Author(s).