Chronic type II interferon promotes tumor growth through mitochondrial RNA-induced type I interferon and prostaglandin synthesis

• 成果类型: Article
• 署名作者: Johnson, Melissa A.; Varanasi, Siva Karthik; Mangalhara, Kailash Chandra; Lande, Kathryn; Rojas, Gladys R.; Esparza-Molto, Pau B.; Reynolds, Mack B.; Olliffe, Neva; Wessendorf-Rodriguez, Karl; Ghosh, Sagnika; Chen, Dan; Moyzis, Alexandra G.; Donnelly, Matthew P.; Chinn, Rebecca; Xu, Ziyan; Grae, Kym J.; Tripple, Victoria; LaPorta, Michael A.; Metallo, Christian M.; Hargreaves, Diana C.; Kaech, Susan M.; Shadel, Gerald S.
• 署名单位: Salk Institute; University of California System; University of California San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Salk Institute; University of Massachusetts System; University of Massachusetts Worcester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aec0002
• 发表日期: 2026-09-10
• 页码: 1107-1116
• 关键词: cancer; cyclooxygenase-2; macrophage; expression; resistance; release

摘要

Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells. Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system. In this study, we sought to determine the cellular mechanisms underlying this switch from antitumorigenic to protumorigenic interferon activity. We show that chronic type II interferon (IFN-II) exposure distinctively induced tumor growth by activating a type I interferon (IFN-I) response mediated by release of double-stranded mitochondrial RNA (ds-mtRNA) into the cytoplasm. This IFN-I signal synergized with IFN-II to enhance tumor growth by increasing immunosuppressive prostaglandin E2 (PGE2) synthesis through increased cyclooxygenase 2 expression. Elimination of PGE2 synthesis in immunotherapy-resistant melanoma cells restored their responsiveness to anti-PD1 treatment, indicating that this covert mtRNA-IFN-prostaglandin pathway could be a therapeutic target to combat immunotherapy resistance.