A new study has identified a molecular cue that cancer cells use to exhaust the T cells responsible for destroying them, and the findings show that shutting down this signal may help restore the body's immune defenses. The work, led by researchers at Weill Cornell Medicine and published Nov. 17 in Nature Immunology, reveals that tumors do more than slip past the immune system. They can also alter immune cells in ways that reduce their ability to fight back.
"Our dream is to make immune-based therapies available to every patient. To overcome resistance, we must unlock the power of exhausted T cells, reviving them to destroy cancer. This discovery moves us closer to a future where the immune system itself defeats tumors," said the study's co-senior author, Dr. Taha Merghoub, Margaret and Herman Sokol Professor in Oncology Research, and professor of pharmacology at Weill Cornell Medicine.
Why Immunotherapies Sometimes Fall Short
Modern immunotherapies have reshaped cancer treatment by boosting the body's own defense system. However, not all patients benefit, and even those who do may see their response diminish as their T cells become overworked.
"Our findings reveal a completely new way that tumors suppress the immune system," said co-senior author Dr. Jedd Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center, professor of medicine at Weill Cornell and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. "By blocking this pathway, we can help exhausted T cells recover their strength and make existing immunotherapies work better for more patients."
How T Cells Lose Their Ability to Fight
T cell exhaustion occurs when the immune system faces long-term infections or persistent tumor activity. Under these conditions, T cells can still recognize harmful cells, yet they stop attacking. "So, they're primed, but they're no longer killing," explained Dr. Merghoub, who is also deputy director of the Meyer Cancer Center and co-director of the Parker Institute of Cancer Immunotherapy at Weill Cornell. He added that although this loss of activity seems harmful, it can prevent uncontrolled inflammation and sepsis.
Earlier studies showed that a surface protein called PD1 contributes to this exhaustion process. Drugs known as checkpoint inhibitors target PD1 and have already proven effective at reviving T cells in cancers such as melanoma.
CD47 Emerges as a Second Immune Brake
The research team set out to determine whether CD47, a molecule found on cancer cells, also plays a role in pushing T cells toward exhaustion. Previous work revealed that tumors use CD47 as a "don't eat me signal" to prevent certain immune cells from ingesting them.
What surprised the scientists was discovering that T cells themselves display CD47. "When T cells are activated, they express CD47. And when they get exhausted, they increase CD47 to very high levels," Dr. Merghoub said.
Experiments showed that mice lacking CD47 had slower tumor growth, suggesting the exhaustion effect came from CD47 on immune cells rather than on cancer cells. In further tests, T cells missing CD47 were more effective against melanoma tumors than T cells that still carried the protein.
Thrombospondin-1 and CD47 Work Together to Exhaust T Cells
The team then investigated how cancer cells might manipulate this process. Their attention turned to thrombospondin-1, a large protein produced by metastatic cancer cells that binds to CD47. When mice were engineered to lack thrombospondin-1, their T cells showed fewer signs of exhaustion.
"That was the real eureka moment," said Dr. Merghoub. "It showed us that CD47 and thrombospondin are clearly key players because eliminating either one gives you the same effect."
Disrupting the Exhaustion Signal With TAX2
To understand the interaction more closely, the researchers used a peptide called TAX2, which was designed to block the connection between CD47 and thrombospondin-1. The results were clear: TAX2 helped maintain T cell activity and slowed tumor progression in mice with melanoma or colorectal cancer.
T cells in treated animals stayed more active, released more immune-boosting cytokines, and were better at entering tumors. TAX2 also enhanced the effectiveness of PD1 immunotherapy in colorectal tumor models.
"We used the TAX2 peptide as a proof-of-concept to confirm that disrupting the crosstalk between TSP-1 and CD47 prevents T cell exhaustion in mice with tumors," said Dr. Chien-Huan (Gil) Weng, an instructor in pharmacology and the study's lead author. "Next, we plan to study both upstream and downstream modulators that regulate the TSP-1:CD47 pathway and develop means to selectively, effectively and safely disrupt this pathway to improve T cell-based cancer immunotherapy."
Toward Stronger, Longer-Lasting Immune Therapies
Blocking this interaction could serve as an effective therapy by itself and may also help sustain tumor-targeting T cells in patients who are at risk of becoming resistant to current immune checkpoint treatments. According to Dr. Merghoub, early experiments in animal models suggest that inhibiting both PD1 and CD47 creates T cells that are significantly better at destroying cancer cells. "We plan to explore this therapeutic angle."
Many Weill Cornell Medicine physicians and scientists collaborate with external organizations to advance scientific research and provide expert guidance. These relationships are disclosed publicly for transparency. Profiles for Dr. Taha Merghoub and Dr. Jedd Wolchok contain details about these affiliations.
This research received support from the National Institutes of Health grant #R01-CA249294; National Cancer Institute, Cancer Center Support Grant P30CA008748; the Department of Defense grants W81XWH-21-1-0101 and W81XWH-20-1-0723; Swim Across America; the Ludwig Institute for Cancer Research; the Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering; the Cancer Research Institute; the Parker Institute for Cancer Immunotherapy; and the Breast Cancer Research Foundation grants BCRF-22-176 and BCRF-23-176.
