Study Reveals How Tumors Exhaust T Cells

Recent research led by Weill Cornell Medicine scientists has uncovered a molecular signal responsible for exhausting T cells, while demonstrating how silencing this signal can restore the body’s own defenses. Published in Nature Immunology, the study reveals that tumors not only hide from the immune system but can actively reprogram immune cells and halt their attack. According to Taha Merghoub, co-senior author of the study, “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.”

Immunotherapy has changed cancer treatment in recent years, enabling the body’s natural defenses to fight tumors. Despite these breakthroughs, some patients do not respond, or their immune cells lose effectiveness over time. “Our findings reveal a completely new way that tumors suppress the immune system...By blocking this pathway, we can help exhausted T cells recover their strength and make existing immunotherapies work better for more patients,” explains co-senior author Jedd Wolchok.

T cell exhaustion happens when chronic exposure to tumors or infections triggers the immune response until T cells can recognize threats but stop attacking them. Dr. Merghoub explains that this cellular “surrender” not only protects against uncontrolled inflammation but also limits immune response in cancer. Past research established that the protein PD1 dampens T cell activity and that drugs targeting PD1 can revive immune responses in certain cancers.

The new study investigated whether CD47 molecules on cancer cells contributed to T cell exhaustion. While CD47 had been dubbed the “don’t eat me signal” for helping tumors evade other immune cells, researchers found that its presence on T cells themselves rose sharply when those T cells became exhausted. Mice lacking CD47 showed delayed tumor growth, indicating that CD47 on immune cells—not cancer cells—was at fault. Removal of CD47 from T cells improved their cancer-fighting abilities in melanoma models. 

Focusing on thrombospondin-1, a protein produced by metastatic cancer that binds to CD47, researchers showed that mice lacking thrombospondin-1 also resisted T cell exhaustion. Disruption of the CD47–thrombospondin-1 connection using a TAX2 peptide helped T cells stay active, produce more cytokines, and infiltrate tumors better. Combined with PD1 immunotherapy, this approach slowed tumor progression in mice.

Ultimately, targeting the CD47–thrombospondin-1 interaction could not only boost T cell activity alone but also improve the efficacy of existing checkpoint inhibitor therapies for cancer.