Indeed, one of cancer’s crafty tricks involves manipulating the host’s immune cells to safeguard the tumors instead of fighting them. And while the immune system would win most of the time in a fair fight between it and cancer, well, cancer doesn’t fight fair—it gains the upper hand by deploying an array of underhanded tricks.
Cancer creates a microenvironment around itself to sap nutrients and weakens the immune response at the location, promoting its growth. One of the sneakiest ways it performs this is by hijacking the function of immune cells known as regulatory T cells (Tregs).
Usually, these cells play the vital role of keeping the immune system from attacking the body’s cells, a condition that would lead to autoimmune diseases. However, some cancers selectively let Tregs into their microenvironment. Once in, they have them fight off immune cells that come to kill cancer cells. Keeping immune cells focused on tumors is a challenge across the field: UCLA’s experimentally engineered cord-blood T cells are built to hunt cancers without attacking healthy tissue.
But now, researchers at the Dana-Farber Cancer Institute, Massachusetts General Hospital (MGH), and other Boston-area research centers have figured out how to transform these cells back into cancer killers that are still allowed passage into the cancer’s microenvironment. Like this, they enter and kill cancer from the inside and help other immune cells chip in.
It’s a real-life plot deserving of a classic spy story: the team turned the tables on glioblastomas, the most aggressive and devastating type of brain cancer that’s rapidly fatal. Most patients don’t live beyond two years of diagnosis despite severe therapies like whole-brain radiation, brain surgery, and chemotherapy.
Even existing drugs called immune checkpoint blockers (ICBs)—revolutionary cancer drugs that have helped treat patients with solid tumors, non-small-cell lung cancer, and malignant melanoma—haven’t benefited patients with glioblastoma. ICBs work by detaching the brake system on the immune system, enabling previously dormant resistant cells to recognize, assault, and destroy mutated, malignant cells while causing minimal damage to normal tissues.
But glioblastomas wreak havoc with the immune system by altering the landscape surrounding and within the tumor (the tumor microenvironment). They reorganize immune cells, blood vessels, and tissue structural proteins into an abnormal glioblastoma-promoting environment, effectively impeding the action of ICBs.
Lead author of the study, Rakesh K. Jain, Ph.D., the director of Steele Laboratories and the Department of Radiation Oncology, MGH director, and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School explained, “These abnormalities promote a suppressive environment for the immune system, which blocks tumor-fighting immune cells at the tumor border while allowing infiltration of tumor-promoting immune cells known as regulatory T cells, or Tregs. Among elements of the tumor microenvironment, we exploited the preferential accumulation of Tregs in glioblastoma by therapeutically altering their function—a strategy known as reprogramming—to make them kill cancer cells instead of protecting them. Because Tregs already present in these tumors can be reprogrammed, this strategy does not rely on additional recruitment of anti-tumor immune cells—another frequent barrier to successful immunotherapy in brain tumors.”
The team tested the method on mice with human glioblastoma. They employed an antibody called αGITR, which reprogrammed the cancer-defending Tregs into cancer-fighting CD4 effector T cells. The team backed this with ICBs, which help raise the immune system. The combination resulted in a substantial survival benefit in mouse models of human glioblastoma.
The treatment extended the animals’ survival times. Not only were the tumors wholly eradicated in some cases, but when the scientists reintroduced cancer cells into the mice, their immune systems were still primed to fight the disease off.
Co-author Dai Fukumura, MD, Ph.D., the Steele Labs’ deputy director, commented, “Importantly, some of these mice not only rejected tumors but also developed a long-term immunity against glioblastoma.”
While their findings are promising and support the use of αGITR antibodies in combination with ICBs, they caution that the results are only in mice and may not carry across to humans. Nevertheless, further testing could lead to new possibilities for using immunotherapy to treat brain cancers—methods that traditionally haven’t responded well to the technique.
Retraining tumor-corrupting immune cells is a strategy that keeps paying off. In 2026, NUS researchers took the same principle to breast cancer, showing that brief magnetic pulses can reprogram tumor-protecting macrophages into cancer-eating cells, eradicating tumors in 75 percent of preclinical models without chemotherapy.
