Mitochondrial RNA Drives Resistance to Immunotherapy, Potentially Opening a New Treatment Path

Mitochondrial RNA has been identified as a key cause of tumor resistance to immunotherapy.

According to Azure Life Science on the 22nd (local time), a research team at the Salk Institute found that mitochondrial ribonucleic acid (mtRNA) in cancer cells is involved in the process by which interferon’s anticancer effects are reversed and instead help tumors grow. The study was published in the international journal Science.

Interferon is a signaling protein that recruits immune cells to eliminate cancer cells. It has been used in immunotherapy since 2011 and has changed treatment outcomes for many patients, but many tumors either do not respond from the outset or develop resistance after treatment.

The researchers compared tumor growth after exposing mouse melanoma cells to interferon for 24 hours (acute) or 28 days (chronic). Cells exposed chronically grew more aggressively after transplantation and metastasized to the liver, while the immune environment within the tumors shifted to a state of suppressed immune activity.

Further analysis showed that chronically exposed melanoma cells released mitochondrial genetic material into the cytoplasm. When an intracellular sensor that detects viral infections recognized this material, type 1 interferon was produced even though no virus was present.

The two interferon signals subsequently increased cyclooxygenase 2 (COX-2) activity, promoting production of prostaglandin E2 (PGE2), a lipid molecule that suppresses immunity. Conversely, blocking this sensing pathway or the release of mitochondrial material prevented the secondary interferon response.

The researchers said that when they blocked PGE2 production using conventional anti-inflammatory drugs or by removing the related enzyme, tumor growth driven by chronic interferon exposure was reversed and immune activity was restored.

The researchers also confirmed a link to immunotherapy resistance. Melanoma cells that did not respond to antibody-based immunotherapy had high COX-2 activity. Removing it restored treatment sensitivity in 9 of 10 mice, completely eliminating their tumors. The same pattern was observed in several mouse melanoma cell lines and human melanoma cells.

The researchers said the findings could offer a strategy to improve treatment outcomes for patients with cancer who no longer respond to existing immune checkpoint inhibitors.