Salk Team Maps How Chronic Interferon II Drives Immunosuppression and Anti-PD1 Resistance in Melanoma
核心洞察
Salk Institute researchers identified a mitochondria-centered pathway in which chronic interferon II (搜索) exposure causes melanoma (搜索) cells to produce prostaglandin E2 and suppress immune attack.
In mouse melanoma (搜索) models, blocking prostaglandin E2 synthesis restored immune recognition of tumors and reversed anti-PD1 (搜索) resistance, with complete regression in nine of 10 mice.
The pathway links mitochondrial RNA release to cyclooxygenase 2 (搜索) activity, explaining how interferons shift from anti-cancer to pro-cancer signaling over time.
A Salk Institute research team has uncovered a mitochondria-centered pathway that explains how chronic exposure to interferon II (搜索) transforms the signaling protein from an anti-cancer ally into a driver of immunosuppression and tumor growth. The findings, published in Science on September 10, 2026, also show that interrupting this pathway can reverse resistance to anti-PD1 (搜索) immunotherapy in mouse melanoma (搜索) models.
"Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field," said 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."
The work was funded by federal research grants from the National Institutes of Health and private philanthropy.
From immune first responder to tumor promoter
Interferons are pro-inflammatory signaling proteins that recruit specialized immune cells such as T cells and B cells to destroy cancer cells. This response is a critical early step in the body's fight against cancer, but chronic interferon exposure can invert its effect.
Shadel's laboratory has long studied interferons in the context of mitochondria, having previously discovered that mitochondria trigger interferon responses by releasing mitochondrial genetic material (mtDNA) into the rest of the cell. For this study, the team reversed the question, asking how interferons affect mitochondria rather than the other way around.
To answer it, the researchers exposed melanoma (搜索) cells to interferon I (搜索) or interferon II (搜索) for either acute or chronic periods. Acute exposure produced little change in mitochondria, but chronic exposure led to measurable changes in their energetic function. When these melanoma cells were transferred into a mouse model, chronic interferon II exposure unexpectedly enhanced tumor growth.
mtRNA release, COX-2 and prostaglandin E2
The team then traced the cellular mechanism behind the accelerated tumor growth. They found that interferon II (搜索) causes mitochondrial genetic material (mtRNA) to leave the mitochondria, where the rest of the cell perceives it as an invader and produces interferon I (搜索) in response. Interferons I and II then act together to boost levels of the enzyme cyclooxygenase 2 (搜索), which increases synthesis of the bioactive lipid prostaglandin E2.
That raised the question of whether prostaglandin E2 is the immunosuppressive effector. To test it, the researchers made melanoma (搜索) cells incapable of synthesizing the lipid.
Reversing anti-PD1 resistance
Anti-PD1 (搜索) immunotherapies, among the most widely used immunotherapies, work by blocking a signal that cancer cells use to keep immune cells from attacking the tumor. Tumors can nonetheless suppress the immune system through other pathways and continue growing despite treatment.
"Chronic interferon exposure is a major factor in immunotherapy resistance," said first author Melissa Johnson, a graduate student researcher in Shadel's lab. "We wondered whether cancer cells that have become resistant to anti-PD1 (搜索) therapy were upregulating the immunosuppressive mitochondria-centered pathway we identified, and whether that pathway is a viable target for combating immunotherapy resistance."
Blocking prostaglandin E2 synthesis in mouse melanoma (搜索) cells restored the immune system's ability to see and fight the cancer cells. Moreover, blocking prostaglandin E2 reversed resistance to anti-PD1 (搜索) therapy: in nine of 10 mice, tumors completely regressed and did not return, even though the tumors had previously been resistant to immunotherapy.
Implications for cancer biology
The findings demonstrate potential for future clinical translation, offering a possible way to sustain the immune system's attack on cancer 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," Shadel said, "and also conveys the importance of integrating mitochondrial signaling functions into cancer studies."
The work was supported by National Institutes of Health grants R01 CA228211, R01 CA216101, R01 CA285867, R21 AI151562, F31CA278581, T32GM133351, T32CA009370-39 and F30HL178290, along with the 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.