Researchers at Weill Cornell Medicine report that tumors exploit a CD47–thrombospondin-1 signal to push T cells into exhaustion, and that interrupting the interaction restores T cell activity and slows tumor growth in mouse models. The study was published on November 17, 2025, in Nature Immunology.
Researchers at Weill Cornell Medicine have identified a molecular pathway that tumors use to wear out cancer-fighting T cells, and showed that blocking the signal can keep these cells active in mice. The work, published November 17, 2025, in Nature Immunology, points to a potential strategy for improving existing immunotherapies. (news.weill.cornell.edu)
T cell exhaustion arises during prolonged battles with tumors or chronic infections: cells still recognize threats but stop attacking. “So, they’re primed, but they’re no longer killing,” said co-senior author Dr. Taha Merghoub, a professor at Weill Cornell Medicine. Checkpoint inhibitors that target the PD-1 pathway can reinvigorate some exhausted T cells, particularly in melanoma, but many patients do not respond or develop resistance. (news.weill.cornell.edu)
The study identifies CD47 as a second brake on anti-tumor immunity. The researchers report that T cells upregulate CD47 as they become exhausted. In experiments, mice lacking CD47 developed slower-growing tumors, implicating CD47 on immune cells rather than cancer cells as a driver of the dysfunctional state. The team also found that thrombospondin‑1 (TSP‑1)—a protein produced by metastatic cancer cells—binds CD47 to promote exhaustion; mice engineered without TSP‑1 showed fewer exhaustion markers in T cells. (nature.com)
To disrupt this interaction, the authors used TAX2, a peptide that selectively blocks binding between TSP‑1 and CD47. In mouse models of melanoma and colorectal cancer, TAX2 preserved T cell activity, increased cytokine production, improved tumor infiltration by T cells, and slowed tumor progression. TAX2 also enhanced the effect of PD‑1 immunotherapy in colorectal tumor models, according to the Weill Cornell team. “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 lead author Dr. Chien‑Huan (Gil) Weng. (news.weill.cornell.edu)
Co‑senior author Dr. Jedd Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, said the findings suggest a way to strengthen current treatments: “By blocking this pathway, we can help exhausted T cells recover their strength and make existing immunotherapies work better for more patients.” The researchers plan to explore combination approaches that inhibit both CD47 and PD‑1 to generate more potent, durable anti‑tumor T cells. (news.weill.cornell.edu)
The project was supported by the National Institutes of Health, the Department of Defense, 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. (news.weill.cornell.edu)
