"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.

The compounds, developed with support from FAPESP, are easy to produce and are thought to work by breaking down beta-amyloid plaques that build up in the brains of people with Alzheimer's disease. These plaques form when amyloid peptide fragments accumulate between neurons, triggering inflammation and interfering with communication between brain cells.

Targeting Copper to Break Down Beta-Amyloid Plaques

A study published in ACS Chemical Neuroscience reports that the compounds function as copper chelators. By binding to excess copper found within beta-amyloid plaques, the molecules help degrade these toxic structures and lessen symptoms associated with the disease. Tests in rats showed that the compound reduced memory impairments, improved spatial awareness, and enhanced learning ability. Biochemical analysis also revealed a reversal in the pattern of beta-amyloid plaques.

"About a decade ago, international studies began to point to the influence of copper ions as an aggregator of beta-amyloid plaques. It was discovered that genetic mutations and changes in enzymes that act in the transport of copper in cells could lead to the accumulation of the element in the brain, favoring the aggregation of these plaques. Thus, the regulation of copper homeostasis [balance] has become one of the focuses for the treatment of Alzheimer's," explains Giselle Cerchiaro, a professor at the Center for Natural and Human Sciences at UFABC who coordinated the study.

Designing Molecules That Reach the Brain

Using this understanding, the research team created molecules that can cross the blood-brain barrier and remove copper from beta-amyloid plaques. Ten candidate molecules were developed, and three advanced to testing in rats with induced Alzheimer's disease. One compound showed particularly strong results for both effectiveness and safety.

This work formed the basis of the doctoral thesis of FAPESP scholarship recipient Mariana L. M. Camargo, the master's thesis of Giovana Bertazzo, and the undergraduate research project of Augusto Farias. A team led by Kleber Thiago de Oliveira at the Federal University of São Carlos (UFSCar) contributed by synthesizing one of the compounds included in the study.

Improvements in Brain Health and Behavior

In experiments with rats, the compound lowered neuroinflammation and oxidative stress and restored copper balance in the hippocampus, the brain region responsible for memory processing. Treated animals also demonstrated better performance in tasks requiring spatial navigation.

Beyond these behavioral improvements, the compound proved non-toxic in both hippocampal cell cultures and the animals themselves, whose vital signs were closely followed throughout the experiments. Computer models confirmed that the compound can cross the blood-brain barrier and reach the areas most affected by Alzheimer's-related damage.

A Potentially Affordable New Direction for Alzheimer's Care

Alzheimer's disease is a complex and multifaceted neurodegenerative condition with no cure and no clearly defined cause. While an estimated 50 million people worldwide are affected, current treatment options are limited and often provide only partial symptom relief or rely on costly therapies such as monoclonal antibodies.

The findings from UFABC have already resulted in a patent application, and the team hopes to secure industry partnerships to begin clinical trials in humans. "It's an extremely simple, safe, and effective molecule. The compound we've developed is much less expensive than available drugs. Therefore, even if it only works for part of the population, since Alzheimer's disease has multiple causes, it'd represent a huge advance over current options," Cerchiaro celebrates.