Protecting the Heart During the Fight Against Cancer

by Amanda Chase, PhD
February 20, 2025

Cancer therapies have revolutionized medicine, offering new hope to millions. But for some patients, these powerful treatments come with an unexpected and deadly side effect—heart damage. Some patients receiving immune checkpoint inhibitors (ICIs), a breakthrough cancer therapy, are developing a serious and often fatal condition known as ICI-mediated myocarditis, a form of heart inflammation. Until now, doctors have struggled to predict or prevent this rare but devastating complication.

A new study from researchers at the Stanford Cardiovascular Institute, recently published in Circulation Research, presents a game-changing discovery that could pave the way for targeted treatments to protect the heart while fighting cancer. Co-first authors Yuhsin Vivian Huang and Yin Sun, with senior author Han Zhu, used advanced genetic and pharmacological models in mice to identify a key player in ICI-mediated myocarditis: a protein called CXCR3. Their findings suggest that blocking this protein could dramatically reduce heart inflammation and improve survival.

ICIs work by unleashing the immune system to attack cancer cells. Sometimes, the immune system gets too aggressive, mistakenly attacking healthy organs, including the heart. This study reveals that a specific group of immune cells, called CXCR3+ T cells, flood the heart and trigger severe inflammation. At the same time, certain macrophages, immune cells that usually fight infection, send chemical signals (CXCL9/10) that pull even more T cells into the heart, making the damage worse.

The research team used two different mouse models to closely mimic how ICI myocarditis develops in humans. In one model, the mice were genetically engineered to lack PD-1, a key immune checkpoint, leading to uncontrolled immune activation. In the other, mice were treated with the same ICIs used in human cancer patients. In both models, the scientists observed a dramatic increase in CXCR3+ T cells and CXCL9/10+ macrophages in the heart, mirroring what has been seen in human patients.

As ICIs become more widely used in cancer treatment, understanding and addressing their cardiovascular side effects is more important than ever. This study lays the foundation for future studies in chemokine and chemokine receptor therapies in the heart and other organs that are affected by T-cell-mediated inflammation.

Other Stanford Cardiovascular Institute researchers on the team are Harrison Chou, Noah Wagner, Maria Rosaria Vitale, Bruce Xu, Zachary Lin, Corynn Branche, Ronald Witteles, Patricia Nguyen, and Sean Wu. They were joined by other researchers from Stanford: Sarah Waliany, Joel Neal, Heather Wakelee, Edward Graves, and Gerald Berry. In addition, Abraham Bayer and Pilar Alcaide from Tufts University were part of the team, as was Daniel Lee from F. Edward Herbert School of Medicine at Uniformed Services University.