Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy

• Published in: Nature communications Vol. 15; no. 1; pp. 5759 - 17
• Main Authors: Zhou, Hang, Wang, Wenjun, Xu, Hairong, Liang, Yong, Ding, Jiyu, Lv, Mengjie, Ren, Boyang, Peng, Hua, Fu, Yang-Xin, Zhu, Mingzhao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/2; 14; 14/19; 14/34; 38/91; 631/250/2161; 631/250/580; 631/67/1059/2325; 64/60; 96/31; Adenosine Triphosphate - metabolism; Animals; Anticancer properties; Antitumor activity; Apyrase - metabolism; ATP; Autophagy; Autophagy - drug effects; CD47 Antigen - genetics; CD47 Antigen - metabolism; CD73 antigen; Cell activation; Cell Line, Tumor; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Effectiveness; Female; Humanities and Social Sciences; Humans; Immune system; Immunogenicity; Immunotherapy; Immunotherapy - methods; Interferon; Interferon Type I - metabolism; Lymphocytes; Lymphocytes T; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Oxidation resistance; Oxidative metabolism; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Phosphorylation; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Science; Science (multidisciplinary); Signal Transduction; Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50136-z

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.
CD47 blockade can trigger T cell-mediated destruction of immunogenic tumors. Here the authors show that, by reprograming tumor cell metabolism toward OXPHOS for ATP production, tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPa blockade efficacy.