Researchers at the Salk Institute have discovered a cellular pathway explaining how interferons—immune proteins that typically help fight cancer—can instead promote tumor growth and drive immunotherapy resistance. According to the study, prolonged exposure to interferon II triggers mitochondrial dysfunction and produces prostaglandin E2 (PGE2), a molecule that suppresses anti-tumor immune responses.
How Interferons Shift From Anti-Cancer to Pro-Cancer
Interferons are pro-inflammatory signaling proteins that normally recruit immune cells, such as T cells and B cells, to attack cancer cells. However, according to findings from the Salk Institute, chronic exposure to these proteins can reverse their protective effects.
In experiments where melanoma cells were exposed to interferon I or interferon II, acute exposure produced little detectable change in cellular powerhouses. In contrast, chronic exposure altered mitochondrial energy-producing function. When researchers transferred these chronically exposed melanoma cells into mice, tumor growth unexpectedly increased.
Did you know? Gerald Shadel, professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk, noted that understanding why interferons transition from “good” to “bad” offers a new pathway for therapeutic advantage.
The Mitochondrial Escape Mechanism
The research team investigated the exact mechanism driving this transition. According to the study, interferon II causes mitochondrial RNA (mtRNA) to escape from the mitochondria into the main body of the cell.
The cell misinterprets this escaped genetic material as an external viral threat. That false alarm triggers the production of interferon I. Both interferons then elevate levels of cyclooxygenase 2, an enzyme responsible for producing the bioactive lipid PGE2. Once manufactured, PGE2 actively suppresses immune activity within the tumor microenvironment, allowing cancer cells to evade detection.
Targeting Immunotherapy Resistance in Preclinical Models
The discovery sheds light on why many patients eventually develop resistance to anti-PD-1 immunotherapies, which are widely deployed cancer treatments.
“Chronic interferon exposure is a major factor in immunotherapy resistance,” says first author Melissa Johnson, a graduate student researcher in Shadel’s lab. The team tested whether blocking this pathway could restore treatment efficacy. By preventing melanoma cells in mice from producing PGE2, the researchers successfully restored the immune system’s ability to recognize and attack the cancer.
This targeted intervention reversed resistance to anti-PD-1 treatment. According to the Salk Institute data, tumors completely regressed and did not return in nine out of ten mice that had previously resisted immunotherapy.
Research Status: While these preclinical findings highlight a promising route for future treatments, further research is required before this approach can be evaluated in human clinical trials.
Frequently Asked Questions
What causes interferons to promote tumor growth?
According to Salk Institute researchers, prolonged exposure to interferon II damages cellular mitochondria, causing mitochondrial RNA to leak into the cell. This triggers an immune alarm that ultimately produces PGE2, an immunosuppressive molecule.
What is prostaglandin E2 (PGE2) in cancer?
PGE2 is a bioactive lipid produced by cancer cells under chronic interferon signaling. It suppresses immune cell activity inside tumors, helping cancer cells hide from therapies like anti-PD-1 checkpoint inhibitors.
Can this pathway be blocked to improve immunotherapy?
Yes, in preclinical studies with mice, researchers successfully restored immunotherapy sensitivity and achieved complete tumor regression in nine out of ten subjects by preventing melanoma cells from producing PGE2.
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