Targeting Immune Pathways May Help Prevent Neuropathy Caused by Chemotherapy

Chemotherapy-induced peripheral neuropathy (CIPN) affects up to half of cancer patients undergoing treatment, leading to numbness, tingling, and pain in the hands and feet. The lack of effective treatments for CIPN often forces patients to stop chemotherapy early and can greatly impact quality of life. Recent research from Weill Cornell Medicine and Wake Forest University School of Medicine suggests that new strategies targeting specific immune pathways may help to prevent or reduce neuropathy brought on by chemotherapy.

The study found that chemotherapy, particularly paclitaxel, activates a stress response mechanism in immune cells rather than neurons. This mechanism involves the IRE1α pathway, which, once triggered, sends immune cells into an inflammatory state. These activated immune cells migrate to sensory nerve clusters known as dorsal root ganglia, where they release inflammatory molecules that damage nerves, leading to the symptoms associated with CIPN.

Crucially, silencing IRE1α in immune cells—through genetic methods or with a selective IRE1α inhibitor—substantially reduced pain behaviors and nerve fiber loss in mouse models exposed to chemotherapy. Additionally, a drug that inhibits IRE1α and is already in clinical trials for cancer therapy also helped protect nerve function when used alongside chemotherapy in mice.

“Our findings suggest that targeting IRE1α pharmacologically could mitigate neuropathy induced by taxanes, helping patients continue with their chemotherapy without the negative side effects of nerve damage,” explained Juan Cubillos-Ruiz, co-senior author of the study published in Science Translational Medicine. 

To evaluate whether these findings may have clinical application, researchers conducted a small study with women receiving paclitaxel for gynecologic cancers. Blood tests showed that patients who developed severe CIPN had higher activation of the IRE1α pathway in their immune cells even before symptoms occurred. This points to the potential for a blood test to identify patients at risk for developing CIPN—enabling preventive measures, including the use of IRE1α inhibitors, before nerve damage begins.

By focusing on the molecular stress responses driving immune cell inflammation, this approach suggests a promising strategy for decreasing the risk and severity of neuropathy caused by chemotherapy. Targeted therapies and risk assessment through biomarkers like IRE1α activation may help patients continue their treatment with fewer side effects and preserve their quality of life.