Chemotherapy-Induced Neurotoxicity: Molecular Mechanisms, Biomarkers and Emerging Neuroprotective Strategies

Chemotherapy-induced neurotoxicity is a major dose-limiting complication of systemic anticancer therapy that adversely affects neurological function, treatment continuity, and long-term quality of life among cancer survivors. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common manifestation, whereas chemotherapy-related cognitive impairment (CRCI) and selected immune-mediated neurological toxicities increasingly contribute to survivorship-related morbidity. Although these immune-mediated syndromes are distinct from conventional chemotherapy-induced neurotoxicity, they are included because they share several downstream pathogenic mechanisms relevant to biomarker discovery and neuroprotective strategies. This structured narrative review critically synthesizes current evidence on the molecular mechanisms, clinical manifestations, biomarkers, and emerging neuroprotective strategies underlying chemotherapy-induced neurotoxicity. A comprehensive PubMed/MEDLINE search was performed, with emphasis on studies published between 2014 and 2026. Evidence from systematic reviews, meta-analyses, clinical guidelines, randomized controlled trials, prospective clinical studies, and high-quality translational research was critically evaluated. Current evidence indicates that chemotherapy-induced neurotoxicity arises through interconnected mechanisms involving oxidative stress, mitochondrial dysfunction, neuroinflammation, calcium dysregulation, blood-brain barrier disruption, and SARM1-mediated programmed axonal degeneration. Among emerging biomarkers, neurofilament light chain (NfL) demonstrates the greatest translational potential for early detection and monitoring, while inflammatory cytokines, circulating microRNAs, pharmacogenomic markers, cerebrospinal fluid biomarkers, and advanced neuroimaging may improve individualized risk stratification. Although duloxetine remains the only guideline-recommended pharmacological treatment for established painful CIPN, mechanism-based therapies targeting mitochondrial dysfunction, neuroinflammation, oxidative stress, and SARM1 signaling, together with structured exercise and biomarker-guided precision medicine, represent promising translational approaches. However, clinical implementation remains limited by incomplete biomarker validation, heterogeneous study methodologies, and the absence of effective disease-modifying neuroprotective therapies, underscoring the need for large biomarker-guided multicenter clinical trials.