Mitochondrial RNA escape may explain how chronic immune signaling helps tumors grow
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Cancer biology—and, in turn, cancer treatment—have come a long way in the last few decades. Most people recognize this progress in breakthroughs like immunotherapy, a treatment strategy first deployed in 2011 that leverages the body's own immune cells to fight cancer. It has revolutionized the treatment landscape. However, progress doesn't mean all the questions have been answered.
One of those questions is why signaling proteins called interferons, which recruit the immune system to attack cancer cells, start helping tumors grow rather than shrink when they linger too long. A Salk Institute team discovered a novel pathway that links chronic type II interferon exposure to mitochondrial dysfunction that ultimately causes immunosuppression.
By explaining how type II interferon turns from "good" to "bad," the foundational insights provide a path to future therapies that combat immunotherapy resistance.
The study was published in Science on Sept. 10, 2026.
"Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field," says senior author Gerald Shadel, professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk.
"Our study reveals a major reason why interferons transition from 'good' to 'bad,' as well as how we can prevent this switch for therapeutic advantage moving forward."
How does the immune system respond to a tumor?
As soon as a cancer cell appears, the immune system jumps into action—and interferons are among the first responders. Interferons are pro-inflammatory signaling proteins that recruit specialized immune cells (like T cells or B cells) to destroy cancer cells. This is a critical, powerful step in the body's fight against cancer, but chronic exposure to interferons can turn them from an ally to an enemy.
Shadel's lab has been studying interferons for a while—for his team, the context is always mitochondria. His lab first discovered that mitochondria invoke interferon responses through the release of mitochondrial genetic material (mtDNA) into the rest of the cell. The lab's research seeks to uncover the ways mitochondrial dysfunction can lead to inflammation, aging and pathology.
"For this study, we turned our focus around," says Shadel.
"Instead of asking how mitochondria affect interferons, we asked how interferons affect mitochondria. And cancer is a powerful system in which to ask this question, since interferons are so essential to the body's cancer response."
What makes a good immune system response to cancer turn bad?
To determine how interferons affect mitochondria, the team first exposed melanoma cells to type I or type II interferon for either acute or chronic periods. While little happened to mitochondria with acute exposure, chronic exposure led to measurable changes in their energetic function.
The researchers then transplanted these melanoma cells into a mouse model and found that chronic type II interferon exposure unexpectedly enhanced tumor growth.
Next, the team worked to decipher the cellular mechanisms behind the enhanced tumor growth. They found that type II interferon causes mitochondrial genetic material (mtRNA) to leave the mitochondria, where the rest of the cell perceives it as an invader and produces type I interferon in response.
Type I and type II interferons then work together to boost levels of the enzyme cyclooxygenase-2, which increases the synthesis of the bioactive lipid prostaglandin E2.
If prostaglandin E2 is causing immunosuppression, the team asked, what happens if melanoma cells are made incapable of synthesizing it?
Blocking prostaglandin E2 in melanoma cells
Anti-PD-1 immunotherapies are among the most widely used immunotherapies. They work by blocking a signal that cancer cells use to keep immune cells from attacking the tumor. But tumors can also suppress the immune system through other pathways, allowing them to continue growing despite anti-PD-1 treatment.
"Chronic interferon exposure is a major factor in immunotherapy resistance," says first author Melissa Johnson, a graduate student researcher in Shadel's lab.
"We wondered whether cancer cells that have become resistant to anti-PD-1 therapy were upregulating the immunosuppressive mitochondria-centered pathway we identified, and whether that pathway is a viable target for combating immunotherapy resistance."
The researchers blocked the synthesis of prostaglandin E2 in mouse melanoma cells. They found that eliminating this signal restored the immune system's ability to see and fight the cancer cells. What's more, blocking prostaglandin E2 reversed resistance to anti-PD-1 therapies—in nine of 10 mice, the tumors completely regressed and didn't return, even though they were previously resistant to immunotherapy.
How does this study inform future cancer biology and treatment research?
The findings demonstrate potential for clinical translation, offering a way to sustain the immune system's attack on cancer and hope in cases of immunotherapy resistance.
"Our study enriches our understanding of how the immune system attacks cancer cells and can be stymied by other factors in the tumor environment," says Shadel.
"It also conveys the importance of integrating mitochondrial signaling functions into cancer studies."
Publication details
Melissa A. Johnson et al, Chronic type II interferon promotes tumor growth via mitochondrial RNA-induced type I interferon and prostaglandin synthesis, Science (2026). DOI: 10.1126/science.aec0002.
www.science.org/doi/10.1126/science.aec0002
Journal information: Science
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Swati Mestri
Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →
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