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

Additionally, 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 CIPN as an emergent property of combination chemotherapy and establish IL-1R signaling as a context-dependent therapeutic target with translational relevance.