Researchers uncover key mechanism behind chemotherapy-induced nerve damage

(Press-News.org) WINSTON-SALEM, N.C., Oct. 29, 2025 — Scientists at Wake Forest University School of Medicine, in collaboration with researchers at Weill Cornell Medicine, have made a breakthrough in understanding why many cancer patients develop nerve damage after chemotherapy. Their new study reveals that a stress response inside certain immune cells can trigger this debilitating side effect. This discovery could open the door to new ways to prevent or treat nerve damage in cancer patients.

The study was published online today in Science Translational Medicine.

Chemotherapy-induced peripheral neuropathy is a common and often severe side effect of cancer treatment, especially with drugs like paclitaxel. It can cause tingling, numbness and pain in the hands and feet, sometimes forcing patients to stop life-saving treatment early. Up to half of all patients receiving chemotherapy may experience this condition, but until now, the exact cause has remained a mystery.

To better understand this nerve toxicity that could be painful, scientists used a well-established mouse model that closely reflects the nerve problems experienced by people undergoing cancer treatment. This model allowed researchers to observe how a specific immune cell pathway, known as IRE1α, contributes to triggering inflammation that led to neurotoxicity and pain. By blocking the IRE1α pathway in the immune cells of these mice, either through genetic techniques or with an IRE1a inhibitor, the team was able to prevent the development of nerve damage, pain and toxic inflammation.

The researchers also studied a group of patients from Atrium Health Wake Forest Baptist’s National Cancer Institute-designated Comprehensive Cancer Center. The patients were receiving chemotherapy for gynecological cancers, collecting blood samples before and after treatment to measure IRE1α activity in their immune cells. They found that patients with higher IRE1α activation were more likely to develop severe neuropathy due to chemotherapy, directly linking the mouse model findings to patient outcomes.

Key Findings

Chemotherapy activates a stress sensor (IRE1α) in immune cells, triggering inflammation and nerve damage. Blocking this sensor in mice prevented nerve pain and damage, suggesting a new treatment target. In patients, higher activation of this stress sensor in blood cells was linked to more severe nerve symptoms and also to the initiation of neuropathy symptoms. “Our research shows that a stress response inside immune cells is a key contributor to chemotherapy-induced neuropathy that could be painful and debilitating. By targeting this pathway, we may be able to protect patients from one of the most challenging side effects of cancer treatment,” said E. Alfonso Romero-Sandoval, M.D., Ph.D., professor of anesthesiology at Wake Forest University School of Medicine and the study’s corresponding author. “Our study opens the opportunity to further explore if this pathway could be used to predict what patients will develop this condition and therefore could help clinicians implement patient-tailored treatments,” Romero-Sandoval said.

The discovery could lead to new drugs that block this pathway, helping patients stay on their cancer treatment without suffering from painful side effects.

According to Romero-Sandoval, who is a member of the Atrium Health Wake Forest Baptist Comprehensive Cancer Center, this is the first study to show that the IRE1α stress sensor in immune cells is directly linked to nerve damage from chemotherapy.

The team plans to conduct larger clinical studies to confirm these findings and test whether the IRE1α pathway could be used as a biomarker for disease progression and if drugs that block this stress sensor can safely prevent or reduce nerve damage in cancer patients. They also hope to explore whether this approach could help with other types of nerve pain. Interestingly, an IRE1a inhibitor is currently in clinical trials to improve anti-cancer effects of chemotherapy, including paclitaxel.

This research was supported by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, as well as the U.S. Department of Defense. Additional support came from the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. 

Wake Forest University School of Medicine, the academic core of Advocate Health, advances cancer care through more than 1,000 clinical trials nationwide. At the heart of this work is the NCI-designated Comprehensive Cancer Center at Atrium Health Wake Forest Baptist, where members lead research and innovation as a cornerstone of progress for over 50 years.

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