Chronic type II interferon promotes tumor growth through mitochondrial RNA–induced type I interferon and prostaglandin synthesis
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 E 2 (PGE 2 ) synthesis through increased cyclooxygenase 2 expression. Elimination of PGE 2 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.
Authors
- Gladys R. Rojas
- Kathryn Lande (ORCID: https://orcid.org/0009-0005-1613-8981)
- Kailash Chandra Mangalhara (ORCID: https://orcid.org/0000-0001-7412-3095)
- Mack B. Reynolds (ORCID: https://orcid.org/0000-0002-8445-3749)
- Karl A. Wessendorf-Rodriguez (ORCID: https://orcid.org/0000-0002-4136-8771)
- Pau B. Esparza‐Moltó (ORCID: https://orcid.org/0000-0001-9034-1121)
- Ziyan Xu (ORCID: https://orcid.org/0000-0003-1270-135X)
- Christian M. Metallo (ORCID: https://orcid.org/0000-0003-2404-3040)
- Neva Olliffe
- Alexandra G Moyzis (ORCID: https://orcid.org/0000-0002-3912-3660)
- Sagnika Ghosh (ORCID: https://orcid.org/0000-0003-2883-7008)
- Siva Karthik Varanasi (ORCID: https://orcid.org/0000-0001-5797-2984)
- Matthew P. Donnelly (ORCID: https://orcid.org/0000-0002-4667-8808)
- Victoria Tripple
- Gerald S. Shadel (ORCID: https://orcid.org/0000-0003-2899-8717)
- Susan M. Kaech (ORCID: https://orcid.org/0000-0003-1674-1420)
- Melissa Johnson (ORCID: https://orcid.org/0000-0002-6913-6059)
- Diana C. Hargreaves (ORCID: https://orcid.org/0000-0003-3724-3826)
- Michael A. LaPorta (ORCID: https://orcid.org/0009-0001-0461-5614)
- Susan M. Kaech (ORCID: https://orcid.org/0000-0001-5156-6635)
- Kym J. Grae
- Rebecca R Chinn (ORCID: https://orcid.org/0000-0002-2768-8058)
Institutions
- Salk Institute for Biological Studies (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- University of California San Diego (US)
- University of California San Diego Medical Center (US)
- La Jolla Bioengineering Institute (US)
Publication Details
- Journal
- Science
- Published
- 2026-09-10
- DOI
- https://doi.org/10.1126/science.aec0002
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00