Something strange happens to nearly half of all people who receive chemotherapy, and for decades, doctors could not explain why it occurred or how to stop it from happening. Patients would arrive at their oncology appointments ready to fight cancer, only to find themselves battling a second enemy that emerged from the treatment itself. Tingling sensations would begin in their fingertips and toes, followed by numbness that spread like cold water through their hands and feet, and then came the pain that made simple tasks feel impossible.

Chemotherapy-induced peripheral neuropathy, known as CIPN among medical professionals, affects up to half of all patients receiving chemotherapy and forces many of them to reduce their doses or abandon treatment altogether. Imagine fighting for your life against cancer while your own treatment creates suffering so severe that you must choose between continuing therapy and preserving your quality of life. For years, scientists believed they understood what caused CIPN, pointing to damage occurring inside nerve cells as the obvious explanation for why patients experienced such debilitating symptoms.

But what if everyone had been looking in the wrong place all along?

New research published in Science Translational Medicine has challenged assumptions that guided CIPN research for years, and the answers scientists found came from an unexpected source within the body. A team from Weill Cornell Medicine and Wake Forest University School of Medicine followed a molecular trail that led them away from neurons and toward a different type of cell entirely, and their discovery could change how doctors approach one of chemotherapy’s most limiting side effects.

Blaming Nerves May Have Been Wrong All Along

For years, researchers focused their attention on what chemotherapy drugs like paclitaxel did to neurons, examining how these medications stabilized microtubules and disrupted mitochondrial function within nerve cells. Scientists reasoned that since patients experienced nerve-related symptoms, the problem must originate in the nerves themselves, and this assumption shaped how the medical community approached CIPN research and treatment development. Yet despite decades of study, effective treatments remained elusive, and patients continued to suffer without adequate options for relief.

Dr. Juan Cubillos-Ruiz and his colleagues at Weill Cornell Medicine decided to investigate a different possibility based on their previous work with immune cells and pain pathways. Their earlier research had shown that certain stress responses in immune cells could promote pain after surgery and inflammation in mouse models, which raised an interesting question about whether similar mechanisms might operate during chemotherapy treatment.

What they discovered surprised them and challenged conventional thinking about CIPN’s origins. “We uncovered a molecular mechanism that maps specifically to immune cells, not neurons,” said Dr. Cubillos-Ruiz, who serves as the William J. Ledger, M.D. Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. “This provides strong evidence that chemotherapy-induced neuropathy is not just a nerve issue but an immune-mediated inflammatory process driven by cellular stress responses.”

Dr. E. Alfonso Romero-Sandoval, professor of anesthesiology at Wake Forest University School of Medicine, co-led the research that would reframe how scientists understand CIPN development.

Inside Your Cells Lives an Alarm System

Deep within your immune cells exists a molecular sensor called inositol-requiring enzyme 1α, or IRE1α, which monitors the health of a cellular compartment known as the endoplasmic reticulum. When cells encounter stress that threatens their normal function, IRE1α activates and sets off a cascade of responses designed to help the cell cope with the challenge it faces. Think of IRE1α as an alarm system that detects danger and triggers protective measures, though sometimes those protective measures create problems of their own.

IRE1α works together with a protein called XBP1 as part of a signaling pathway that scientists had already connected to pain responses in other circumstances. Previous studies from Dr. Cubillos-Ruiz’s laboratory demonstrated that IRE1α-XBP1 signaling in immune cells promoted pain after surgical procedures and during inflammatory conditions in mouse models. Armed with this knowledge, the research team hypothesized that paclitaxel might activate this same alarm system in ways that contributed to CIPN development.

Understanding how IRE1α operates requires appreciating that immune cells do far more than fight infections, as they also respond to chemical signals throughout the body and can generate inflammation that affects tissues far from any infection site. When chemotherapy drugs circulate through the bloodstream, immune cells encounter these chemicals and must decide how to respond, and sometimes that response creates unintended consequences for the patient.

How Paclitaxel Sets Off a Chain Reaction

Paclitaxel, one of the most common chemotherapy drugs used to treat various cancers, triggers a specific sequence of events inside immune cells that researchers can now trace step by step. When macrophages and other myeloid cells encounter paclitaxel circulating in the blood, these immune cells begin producing large amounts of reactive oxygen species, which are molecules that place cells under oxidative stress.

Reactive oxygen species accumulation within the mitochondria of immune cells creates endoplasmic reticulum stress that activates the IRE1α alarm system, and this activation pushes immune cells into a highly inflammatory state that differs from their normal function. Macrophages experiencing IRE1α hyperactivation begin producing a cocktail of inflammatory molecules including TNF-α, IL-1β, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2, each of which can irritate and damage surrounding tissues.

These hyperactive immune cells then migrate toward the dorsal root ganglia, which are clusters of sensory neurons that connect your limbs to your spinal cord and serve as relay stations for sensory information traveling from your extremities to your brain. Once inflammatory immune cells reach the dorsal root ganglia, they release their payload of inflammatory molecules directly onto nerve cells, creating the irritation and damage that produces CIPN symptoms. Patients experience pain, heightened sensitivity to cold temperatures, and progressive loss of nerve fibers in their hands and feet as a direct result of this inflammatory assault.

What makes this discovery so significant is that it identifies immune cells rather than neurons as the primary drivers of CIPN, which opens entirely new possibilities for preventing and treating this condition through interventions that target immune cell behavior.

Silencing the Alarm Protected Mice from Pain

Having identified IRE1α activation in immune cells as a potential driver of CIPN, the research team needed to test whether blocking this pathway would protect against nerve damage and pain. Using genetic techniques, scientists created mice whose immune cells lacked functional IRE1α, which allowed them to observe what happened when chemotherapy could not trigger the alarm system in these animals.

Mice without IRE1α in their leukocytes showed remarkable protection against CIPN development when researchers administered paclitaxel according to protocols that reliably produce nerve damage in normal animals. Inflammatory surges that would have occurred in normal mice failed to materialize in the genetically modified animals, and CIPN-related pain behaviors decreased compared to control groups receiving the same chemotherapy treatment.

Examination of dorsal root ganglia from protected mice revealed reduced neuroinflammation compared to normal mice receiving paclitaxel, and nerve fibers remained healthier throughout the treatment period. Scientists could literally see the difference that blocking IRE1α made at the tissue level, with preserved nerve structures in animals whose immune cells could not activate the inflammatory cascade.

A Drug Already in Human Trials Might Help

Genetic modifications that prevent IRE1α function in immune cells cannot be applied to human patients, so the research team needed to find a pharmacological approach that could achieve similar protective effects. Fortunately, drugs that selectively inhibit IRE1α already exist and have entered clinical testing for other purposes, which created an opportunity to test whether these compounds could prevent CIPN in mice.

Researchers administered an IRE1α inhibitor alongside paclitaxel chemotherapy in mouse models and observed what happened compared to mice receiving chemotherapy alone. Animals receiving both drugs displayed reduced pain behaviors compared to those receiving only paclitaxel, and their nerves stayed healthier throughout the treatment period, which suggested that pharmacological IRE1α inhibition could reproduce the protective effects seen in genetically modified mice.

IRE1α inhibitors have already entered Phase 1 clinical trials as cancer treatments because abnormal activation of this pathway can fuel cancer progression and resistance to therapy in patients with advanced solid tumors. “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,” said Dr. Cubillos-Ruiz, who also co-leads the Cancer Biology Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Such dual benefits from a single drug could prove extraordinarily valuable for cancer patients, as Dr. Cubillos-Ruiz noted that combining cancer-fighting effects with nerve protection “could meaningfully improve both the effectiveness of cancer treatment and patients’ quality of life.”

A Blood Test Might Predict Who Will Suffer Most

Translating laboratory findings to human patients requires bridging the gap between mouse models and clinical reality, so the research team conducted a pilot study with women receiving paclitaxel for gynecologic cancers. Scientists collected blood samples from participants before treatment began and during each subsequent chemotherapy cycle, tracking IRE1α-XBP1 pathway activation in circulating immune cells over time.

Analysis of these blood samples revealed a striking pattern that connected immune cell activity to later CIPN development in specific patients. Women who developed severe CIPN symptoms during their treatment course showed higher activation of the IRE1α-XBP1 pathway in their circulating immune cells, and this elevated activation appeared in blood tests taken before patients experienced any neuropathy symptoms.

Early detection of elevated IRE1α-XBP1 activation could eventually allow doctors to identify patients at highest risk for CIPN before nerve damage begins, which would create opportunities for preventive intervention rather than reactive treatment. Patients identified as high-risk through blood testing might receive IRE1α inhibitors alongside their chemotherapy from the beginning of treatment, potentially avoiding CIPN development altogether rather than attempting to manage symptoms after damage has occurred.

What Comes Next for Patients and Researchers

Scientists involved in this research have outlined several priorities for future investigation that could accelerate translation of these findings into clinical practice. Understanding which specific immune cell subsets drive CIPN would allow for more targeted interventions, while evaluating whether paclitaxel activates ER stress sensors in neurons or vascular cells could reveal additional therapeutic targets.

Larger clinical studies will be necessary to validate IRE1α-XBP1 as both a biomarker for predicting CIPN risk and a therapeutic target for preventing its development in chemotherapy patients. Support from the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the U.S. Department of Defense funded this research, and continued investment will be essential for advancing these findings toward clinical application.

For patients currently struggling with CIPN symptoms, this research offers something that has been difficult to find in previous studies of this condition. Beyond identifying a new treatment target, these findings provide validation that CIPN represents a real biological process with identifiable molecular drivers rather than a mysterious affliction without clear cause. Understanding why chemotherapy causes nerve pain represents the first step toward preventing it, and scientists have now taken that step in a direction that could lead to meaningful change for millions of cancer patients worldwide.

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