For many people diagnosed with cancer, treatment with immune checkpoint inhibitors (ICIs)\u00a0has\u00a0dramatically extended lives.\u00a0Some of these treatments, such as Keytruda and Opdivo, have become\u00a0familiar\u00a0brand names.\u00a0<\/p>\n
However,\u00a0for some patients,\u00a0ICI\u00a0cancer\u00a0treatment also\u00a0can\u00a0prompt the immune system to attack heart tissue-a potentially lethal side effect.\u00a0<\/p>\n
Now, scientists at Cincinnati Children’s report discovering a way to dramatically reduce that risk. Details were\u00a0published Feb 20, 2026, in the\u00a0Journal of Experimental Medicine.\u00a0<\/p>\n
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This study makes\u00a0a very important\u00a0discovery that shows how to uncouple anti-tumor efficacy<\/a> from cardiac toxicity. These findings have major implications for treating or avoiding immune related adverse events in cancer patients receiving immune check point blockade.”\u00a0<\/p>\n
Chandrashekhar Pasare, DVM, PhD, director, Division of Immunology at Cincinnati Children’s<\/p>\n
<\/p>\n Pasare\u00a0served as co-corresponding author on the study, along with\u00a0Jeffery Molkentin, PhD, director of the Division of Molecular Cardiovascular Biology.\u00a0First author\u00a0Kathrynne Warrick, an MD-PhD student,\u00a0led the research work.\u00a0<\/p>\n What are ICIs?\u00a0<\/p>\n Immune checkpoint inhibitors work by cutting off\u00a0signals\u00a0from “checkpoint”\u00a0proteins that cancer cells use to hide from the immune system. This allows the body’s T cells to\u00a0recognize and destroy\u00a0tumor cells.\u00a0<\/p>\n Since 2011, when the first drug (Yervoy) was approved in the U.S. for treating metastatic melanoma<\/a>, this form of\u00a0treatment\u00a0has revolutionized outcomes\u00a0for many types of cancer. In fact, the inventors \u2013\u00a0James Allison\u202fand\u202fTasuku Honjo\u202f\u2013 received the Nobel Prize in Medicine in 2018 for their discovery.\u00a0<\/p>\n However, in about\u00a02% of all cancer patients receiving\u00a0ICIs, the treatments\u00a0can cause\u00a0myocarditis-an inflammation<\/a> of heart muscle.\u00a0About half of\u00a0these patients die from this\u00a0complication,\u00a0even if they survive their\u00a0cancer.\u202f<\/p>\n Promising path to prevention\u00a0<\/p>\n To better understand the complication, the research team engineered a new\u00a0mouse model that accurately mimics\u00a0immune checkpoint inhibitor\u2013induced myocarditis.\u00a0Then,\u00a0in a series of advanced experiments, the team pinpointed a key driver of the complication:\u00a0CD8 T cell\u2013derived\u00a0tumor necrosis factor (TNF).\u00a0<\/p>\n Importantly, the team found that this complication from checkpoint inhibitors is not caused by tumors exhausting the body’s cancer-specific T cells, but rather through causing new production of “autoreactive” T cells that see healthy\u00a0cardiac\u00a0muscle cells as targets in addition to cancer cells.\u00a0<\/p>\n The team went on to show, in mice, that blocking TNF signaling specifically through the TNFR2 gene product prevented the inflammatory cycle from starting in the heart.\u00a0<\/p>\n “Checkpoint inhibitors allow TNF signaling to trigger CD8 T-cells that are specific to antigens on cardiac myocytes, which in turn leads to life-threatening arrythmias,” Molkentin says. “We used a targeted TNF blockade method to prevent this cycle in our mouse models. If these results can be replicated in humans, TNF blockade should prevent cardiac toxicity without compromising the anti-tumor benefits of ICIs.”<\/p>\n Next steps\u00a0<\/p>\n More research is needed to\u00a0determine\u00a0if a\u00a0narrowly focused\u00a0TNF inhibitor\u00a0would be safe for human use, and how long a patient might need to take such a drug.\u00a0TNFR2-specific antibodies\u00a0remain\u00a0in development stages.\u00a0The team also wants to\u00a0determine\u00a0whether similar approaches can also prevent immune-related adverse events affecting other organs.\u00a0<\/p>\n Source:<\/p>\n Cincinnati Children’s Hospital Medical Center<\/a><\/p>\n Journal reference:<\/p>\n
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