LA JOLLA (September 10, 2026)—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 and 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 the tumor grow rather than shrink when they linger too long. A Salk Institute team discovered a novel pathway that links chronic interferon II (a family of interferon proteins) exposure to mitochondrial dysfunction that ultimately causes immunosuppression. By explaining how interferon II 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 September 10, 2026, and was funded by both federal research grants from the National Institutes of Health and private philanthropy.
"Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field," says senior author Gerald Shadel, PhD , professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk. "Our study reveals a major reason for 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 the cancer. This is a critical, powerful step in the body's fight against cancer, but chronic exposure to interferons can turn them from ally to 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 to ask this question in, 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 interferon I or interferon II 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 transferred these melanoma cells to a mouse model to find that chronic interferon II exposure unexpectedly enhanced tumor growth.
Next, the team worked to decipher the cellular mechanisms behind the enhanced tumor growth. They found interferon II causes mitochondrial genetic material (mtRNA) to leave the mitochondria, where the rest of the cell perceives it as an invader and produces interferon I to respond. Interferons I and II 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 we make melanoma cells incapable of synthesizing it?
Blocking prostaglandin E2 in melanoma cells
Anti-PD1 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-PD1 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-PD1 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-PD1 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 in the future, offering a potential 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 but can also be stymied by other factors in the tumor environment," says Shadel, "and also conveys the importance of integrating mitochondrial signaling functions into cancer studies."
Other authors and funding
Other authors include Siva Karthik Varanasi, Kailash Chandra Mangalhara, Kathryn Lande, Gladys Rojas, Pau Esparza-Moltó, Mack Reynolds, Neva Olliffe, Karl Wessendorf-Rodriguez, Sagnika Ghosh, Dan Chen, Alexandra Moyzis, Matthew Donnelly, Rebecca Chinn, Ziyan Xu, Kym Grae, Victoria Tripple, Michael LaPorta, Christian Metallo, Diana Hargreaves, and Susan Kaech of Salk.
The work was supported by the National Institutes of Health (R01 CA228211, R01 CA216101, R01 CA285867, R21 AI151562, F31CA278581, T32GM133351, T32CA009370-39, F30HL178290), Glenn Foundation for Medical Research, Cancer Research Institute, NOMIS Foundation, George E. Hewitt Foundation for Medical Research, Fundación Alfonso Martín Escudero, and Spruance Foundation II.
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute's mission is to drive foundational, collaborative, risk-taking research that addresses society's most pressing challenges, including cancer, Alzheimer's, and agricultural vulnerability. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu .
