A systematic review of the neurobiological mechanisms of chemotherapy-induced deficits in executive functions.

A subset of cancer patients and survivors experience cognitive decline during and after chemotherapy, a condition known as chemotherapy-induced cognitive impairment (CICI). Among the most affected domains are executive functions (EFs) - a set of higher-order cognitive processes essential for goal-directed behaviour, including working memory, behavioural flexibility, and inhibition. Emerging evidence suggests that these domains are differentially susceptible to chemotherapy drugs, implicating the selective disruption of distinct neural circuits and neurochemical pathways. To better understand the underlying mechanisms, we conducted a systematic review of rodent models of CICI, focusing on neurobiological alterations associated with chemotherapy and their relationship to EF deficits. A comprehensive search across PubMed, Web of Science, Scopus, and PsycINFO identified 67 eligible papers. Across studies, working memory and problem-solving impairments were most frequently examined and showed the greatest overlap across multiple mechanistic categories, including oxidative stress, mitochondrial dysfunction, neuroimmune dysregulation, impaired plasticity, and altered white matter integrity. Behavioural flexibility was most often linked to disrupted neurogenesis and metabolic imbalance, whereas attention and inhibition showed variable associations with neurotransmission and synaptic markers. Considerable heterogeneity within mechanistic categories reflected interactions among treatment regimen, animal sex, strain, and timing of assessment. Future studies should integrate molecular, cellular, and systems-level analyses within longitudinal and sex-balanced designs to clarify causal mechanisms and guide targeted interventions for preserving cognitive health in cancer survivors.