Distinct neuroinflammatory effects of individual chemotherapeutics shape chemotherapy-induced peripheral neuropathy in a novel mouse model of CVAD combination regimen
Source: Pain
Authors: Hana Starobova, Nicolette Tay, Nikhil Inturi Nageshwar, Ammar Alshamari, Diana Tavares-Ferreira, Samuel Nayler, Asa Andersson, Svetlana Shatunova, Irina Vetter, Publication Date: Mon, 15 Jun 2026 06:00:00 -0400
Pain. 2026 Jun 12. doi: 10.1097/j.pain.0000000000004031. Online ahead of print.
ABSTRACT
Chemotherapy-induced peripheral neuropathy is a common, dose-limiting toxicity of cancer treatment for which no disease-modifying therapies exist. Vincristine-induced neuropathy has been linked to neuroimmune activation and interleukin-1 (IL-1) signaling; however, vincristine is almost exclusively administered as part of combination chemotherapy regimens, where the relevance of IL-1-dependent mechanisms remains poorly defined. Here, we investigate the role of IL-1 receptor (IL-1R) signaling in neuropathy induced by vincristine alone and by the standard CVAD regimen (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in male C57BL6/J mice. IL-1 receptor blockade with the clinically approved antagonist anakinra prevented vincristine-induced mechanical hypersensitivity and attenuated established vincristine-induced peripheral neuropathy, without adverse effects on motor function, hematological parameters, or body weight. In addition, we established a novel CVAD-induced neuropathy model and demonstrate that anakinra partially attenuated CVAD-induced mechanical hypersensitivity and preserved motor function without exacerbating systemic toxicity. Dissection of individual CVAD components identified vincristine as the dominant driver of grip strength decline and IL-1-dependent neuroinflammatory signaling, whereas cyclophosphamide and doxorubicin contributed to sensory hypersensitivity through largely IL-1R-independent mechanisms, and dexamethasone did not induce sensory neuropathy. Immunohistochemistry and transcriptome profiling of peripheral nervous tissue revealed distinct, time-dependent and agent-specific neuroimmune responses with distinct inflammatory and immunosuppressive effects shaping the net CVAD neuroinflammatory phenotype. Together, these findings redefine chemotherapy-induced peripheral neuropathy as an emergent property of combination chemotherapy and establish IL-1R signaling as a context-dependent therapeutic target with translational relevance.
PMID:42294786 | DOI:10.1097/j.pain.0000000000004031
Pubmed ID: pubmed:42294786
Identifiers: pmid:42294786, doi:10.1097/j.pain.0000000000004031,
Paper chosen by Allan Basbaum
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It is generally assumed that chemotherapy-induced neuropathy results from a direct pathophysiological action of the chemotherapy, e.g. vincristine. Here the authors report that co-treatment with anakinra, a clinically approved Il-1 receptor blocker, prevented the vincristine peripheral neuropathy and the associated mechanical hypersensitivity. But as most chemotherapy is combinatorial, they also examined the effects of another common chemotherapy that combines cyclophosphamide, vincristine, doxorubicin, and dexamethasone. With this combination they found that only the vincristine-induced mechanical hypersensitivity was prevented by IL-1 receptor blockade. In contrasat, cyclophosphamide and doxorubicin induced an Il-1 receptor insensitive sensory hypersensitivity. These new findings suggest that chemotherapy-induced polyneuropathy is “an emergent property of combination chemotherapy” and that a focus on combinations that include targeting the IL-1 receptor could have significant translational value.