Radiation Can Help Tumors Hide From the Immune System — Blocking One Protein Flips the Switch, Study Finds

CHICAGO — Radiation therapy kills cancer cells, but it can also quietly reprogramme the immune system to protect the tumor it is meant to destroy. Now researchers at the University of Chicago say they have found the switch behind that unwanted effect — and a way to flip it. Blocking a protein called TET2 turned radiation-reprogrammed immune cells from tumor defenders into tumor attackers in laboratory and animal studies, helping radiation and immunotherapy shrink tumors and control the spread of cancer, according to a study published in Cancer Cell and reported on 31 October 2026.

The finding matters because radiation is given to roughly half to three-fifths of all cancer patients. In some of them, the treatment triggers an expansion of immune cells that dampen the body's defenses, a response linked to shorter survival and a higher risk of metastasis. The new work traces that response to a chain of events that begins in the bone marrow within a day of radiation — and shows, at least in mice, that it can be reversed.

This article reports general research findings and is not medical advice. Anyone concerned about cancer treatment should speak with their own clinician.

Illustration: A beam of radiation therapy directed at a tumor, with immune cells nearby — an artist's impression, not a photograph of a real treatment.

What Happened

The University of Chicago team, led by senior author Ralph Weichselbaum and co-senior author Chuan He, set out to understand why radiation sometimes helps tumors rather than hurting them. Radiation kills tumor cells by damaging their DNA, but it also triggers the expansion of myeloid-derived suppressor cells, known as MDSCs — immune cells made in the bone marrow that suppress the body's defenses against cancer. MDSCs travel to tumors and block CD8-positive T cells, the immune system's main tumor-killing cells. In patients, a rise in MDSCs after radiation is linked to shorter survival and a higher risk of metastasis, the researchers reported.

To find what drives that response, the team analyzed blood samples collected before and after treatment from 33 patients with stage IV non-small cell lung cancer. Those patients were enrolled in a clinical trial at UChicago Medicine combining high-dose, precisely targeted radiation with the immunotherapy drugs nivolumab and ipilimumab. Among all immune cell types, MDSCs carried the highest levels of TET2, an enzyme that removes chemical tags called methyl groups from genetic material. TET2 levels rose further after radiation, most sharply in patients whose cancer did not respond to treatment.

"We noticed in a couple of clinical trials that patients who had elevated TET2 following radiation did worse," Weichselbaum, the Daniel K. Ludwig Distinguished Service Professor and chair of radiation and cellular oncology at UChicago, said in the report. The observation fit earlier findings that patients with TET2 mutations in their blood cells responded better to immunotherapy, suggesting that TET2 may act as a barrier to effective treatment.

In mouse models of colon cancer, melanoma and lung cancer, deleting TET2 only in myeloid cells produced slower tumor growth after radiation, longer survival, and fewer and smaller lung metastases than in normal mice. The team also tested an experimental TET2-blocking drug: combined with radiation, it slowed tumor growth, reduced the number and size of lung metastases, and improved the response to immunotherapy.

Background

The mechanism the team uncovered runs through the bone marrow, not the tumor itself. Radiation activates p53, a protein that senses cellular damage, which in turn switches on TET2. This happens in the bone marrow within a day of radiation, before the reprogrammed cells reach the tumor, the researchers found.

TET2 is best known for removing methyl groups from DNA, but earlier work by He — the John T. Wilson Distinguished Service Professor of Chemistry and of Biochemistry and Molecular Biology at UChicago and a Howard Hughes Medical Institute investigator — showed that it also acts on RNA. In the current study, TET2 removed a mark called 5-methylcytosine (m5C) from chromatin-associated RNAs, which sit on the tightly packaged DNA inside the nucleus. Losing those marks caused the chromatin to compact, silencing genes for type I interferon, a signal that alerts the immune system to threats such as cancer.

"Our previous work showed that an RNA methylcytosine-based pathway is the main mechanism underlying the tumor suppressor function of TET2. It is gratifying to see that the same RNA pathway also accounts for TET2-mediated immune modulation," He said. "It has been a pleasure to collaborate with Weichselbaum's team."

Without TET2, the picture reversed. The RNA marks stayed in place and attracted a protein called MBD6, which helps open chromatin and keep the interferon pathway active. The myeloid cells then developed into a previously undescribed cell type the team named myeloid-derived activating cells, or MDACs. Unlike MDSCs, MDACs present pieces of tumor proteins to CD8-positive T cells and prime them to attack cancer. Transferring MDACs into tumor-bearing mice slowed tumor growth, and a genetic signature of MDACs was linked to better survival in patients across multiple cancer types, according to the study.

Illustration: Immune cells in bone marrow transforming from suppressor cells into activating cells that alert killer T cells — an artist's impression, not a microscope image.

Why It Matters

The study reframes a familiar problem in cancer care. Radiation resistance is often treated as a fixed property of a tumor — some cancers simply do not respond. This work suggests that, at least in part, resistance is a reversible programme running in the patient's own immune cells, one that can be redirected by targeting the epigenetic machinery that controls it. "If you block TET2, you change these immunosuppressive myeloid cells into an immunostimulant, antigen-presenting myeloid compartment that enhances immunotherapy and radiotherapy responses in mice and markedly decreases distant metastasis," Weichselbaum said.

That distinction opens two possible routes forward. The first is TET2 itself: an experimental TET2-blocking drug already showed benefit in combination with radiation in mice. The second is the RNA machinery around it: the chromatin-associated RNAs that control the switch could themselves serve as drug targets, the team said. Either route would aim at the same goal — preventing radiation from creating its own opposition inside the immune system.

The metastasis angle may be the most consequential. Most cancer deaths are caused not by the original tumor but by its spread, and the mouse experiments showed fewer and smaller lung metastases when TET2 was blocked or deleted. "It points the way toward not only targeting TET2, but targeting these chromatin-associated RNAs," Weichselbaum said. "I think it's a way maybe to prevent or treat metastasis." That remains a hypothesis to be tested in people, not a proven treatment — but it gives researchers a concrete mechanism to test, rather than a vague observation that some patients do worse after radiation.

The work also illustrates how immunotherapy and radiation interact. The 33 lung cancer patients in the study received both, and the patients whose cancers did not respond showed the sharpest post-radiation rise in TET2. If TET2 blockade can keep the interferon alarm switched on, it could in principle make both treatments work better together — a combination that oncologists already use, but whose failures are still poorly understood.

Illustration: Scientists in a modern cancer research laboratory examining cell samples — an artist's impression, not a photograph of the study team.

What Happens Next

The immediate next step is clinical testing. The team is now exploring how TET2 inhibitors might be tested together with radiation therapy in patients, according to the report. That step will need to answer questions the current study cannot: whether blocking TET2 in people is safe, what dose and timing work best relative to radiation, and whether the benefit seen in mice translates to longer survival or fewer metastases in patients.

Researchers will also need to confirm the MDAC signature as a biomarker. The team linked a genetic signature of the newly described activating cells to better survival across multiple cancer types, which, if validated, could help identify which patients are most likely to benefit from a TET2-targeted approach — and which are at highest risk of the suppressive response after radiation.

For patients today, the study changes nothing about standard care. No TET2-blocking drug is approved for this use, and the experimental compound tested in mice is not available as a treatment. The value of the finding is as a roadmap: it names the protein, the RNA marks and the cell type involved, giving drug developers specific targets and giving clinicians a measurable signal — post-radiation TET2 levels — to watch as trials are designed.

If those trials succeed, the payoff could extend well beyond one cancer type. Radiation is used across many cancers, MDSC expansion after radiation has been observed broadly, and the mouse experiments covered colon cancer, melanoma and lung cancer alike. A treatment that stops radiation from arming the tumor's defenders would be, in effect, a way to make one of medicine's oldest cancer therapies work the way it was always meant to.

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FAQ

What did the University of Chicago study find?

Radiation activates the protein TET2 in bone-marrow immune cells, locking them into a suppressor state that protects tumors. Blocking TET2 in mice turned those cells into activating cells that help killer T cells attack cancer, improving responses to radiation and immunotherapy.

What are MDSCs and MDACs?

MDSCs, or myeloid-derived suppressor cells, dampen the immune response and block tumor-killing CD8-positive T cells. MDACs, or myeloid-derived activating cells, are a newly described cell type found in this study that present tumor proteins to T cells and prime them to attack.

How was the study done?

The team analyzed blood samples from 33 patients with stage IV non-small cell lung cancer treated with targeted radiation plus nivolumab and ipilimumab, and tested TET2 deletion and an experimental TET2-blocking drug in mouse models of colon cancer, melanoma and lung cancer.

Is there a TET2-blocking treatment available for patients?

No. The TET2-blocking drug used in the study is experimental and has only been tested in mice. The team is exploring how TET2 inhibitors might be tested with radiation therapy in patients, but no such treatment is approved. This article is general information, not medical advice.

Why does this matter for metastasis?

Most cancer deaths result from spread rather than the original tumor. In mice, blocking or deleting TET2 in myeloid cells led to fewer and smaller lung metastases after radiation, suggesting the pathway could one day help prevent or treat metastasis if the effect holds in people.

Sources

• MedicalXpress, "Reversing radiation-activated immune suppression in cancer," 31 October 2026.
• Fei Ji and colleagues, "Myeloid reprogramming generates myeloid-derived activating cells to potentiate radiotherapy and suppress metastasis," Cancer Cell (2026), DOI: 10.1016/j.ccell.2026.08.017.
• University of Chicago Medicine, study report via MedicalXpress, 31 October 2026.