Distinct neuroinflammatory effects of individual chemotherapeutics shape chemotherapy-induced peripheral neuropathy in a novel mouse model of CVAD combination regimen.

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.