Science (New York, N.Y.) · 2026
Chronic type II interferon promotes tumor growth through mitochondrial RNA-induced type I interferon and prostaglandin synthesis.
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Johnson Melissa A, Varanasi Siva Karthik, Mangalhara Kailash Chandra, Lande Kathryn, Rojas Gladys R, Esparza-Moltó 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
Аннотация
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.