Chronic Interferon Exposure Paradoxically Suppresses Tumor Immunity, Offering Path to Resistance

Immunotherapy arrived as a turning point in cancer treatment. When it first entered clinical practice in 2011, it offered something genuinely new: a way to wake up the body's own immune cells and point them at tumors. The strategy worked often enough to reshape how oncologists think about their job. But fifteen years later, the field still grapples with a stubborn paradox. Sometimes the very proteins that should summon immune reinforcement—interferons, the body's chemical alarm bells—end up protecting tumors instead. A team at the Salk Institute has now traced why.

The question Gerald Shadel and his colleagues pursued was deceptively simple: why do interferons, which are anti-cancer when they first appear, become pro-cancer when they stick around? The answer, published in Science on September 10, 2026, points to the mitochondria—the cell's power plants—and a chain of molecular events that ultimately silences the immune system's ability to see and kill cancer cells.

Shadel's lab had spent years studying how mitochondria trigger interferon responses by releasing their own genetic material into the cell. For this study, they flipped the question: instead of asking how mitochondria summon interferons, they asked what happens when interferons flood the system over time. They exposed melanoma cells to interferon I or interferon II in the lab, comparing brief exposure to prolonged exposure. The acute hits caused little change. But chronic exposure damaged the mitochondria's ability to generate energy. When the researchers transplanted these chronically exposed melanoma cells into mice, tumor growth accelerated—the opposite of what should happen when interferons are present.

The mechanism turned out to be a cascade. Chronic interferon II exposure causes mitochondrial RNA to leak out of the mitochondria into the rest of the cell. The cell's defense systems interpret this escaped genetic material as an invasion and respond by producing interferon I. Interferons I and II then work in concert to ramp up production of an enzyme called cyclooxygenase 2, which manufactures a lipid called prostaglandin E2. This molecule is a potent immunosuppressant—it tells immune cells to stand down.

The researchers tested whether blocking prostaglandin E2 could reverse this effect. They engineered melanoma cells incapable of making it and implanted them into mice. The results were striking. Immune cells regained the ability to recognize and attack the tumors. More importantly, blocking prostaglandin E2 restored sensitivity to anti-PD1 immunotherapies—drugs that work by removing the brakes cancer cells place on immune attack. In nine of ten mice, tumors that had been resistant to anti-PD1 treatment completely disappeared and did not return.

This finding addresses a real clinical problem. Anti-PD1 therapies are among the most widely deployed immunotherapies, but many patients develop resistance. Tumors find ways to suppress the immune system through pathways beyond the PD1 checkpoint. Melissa Johnson, the graduate student leading the experimental work, noted that chronic interferon exposure appears to be a major driver of this resistance. The discovery suggests a potential solution: if you can block the prostaglandin E2 pathway, you can restore the immune system's capacity to fight back.

The work is still in mice. Clinical translation remains ahead. But the findings offer a mechanistic explanation for why some patients stop responding to immunotherapy and point toward a specific molecular target that might restore that response. For a field that has learned to harness the immune system but still struggles with resistance, understanding how the body's own alarm signals can backfire offers a concrete path forward.