A three-hit sequential model of chemo-brain: from peripheral inflammation to central oxidative stress and synaptic dysfunction

Chemotherapy-induced central neurotoxicity (CICN), commonly known as "chemo-brain", is a prevalent and debilitating condition in cancer survivors, characterized by persistent cognitive deficits that severely compromise quality of life. Despite extensive research, the pathophysiology of CICN remains fragmented, lacking a unifying model that explains how it progresses from peripheral insult to chronic cognitive consolidation.

This review proposes a novel Three-Hit sequential model to reconceptualize CICN as a dynamic, staged pathological continuum. Unlike existing multi-hit hypotheses that largely describe cumulative or concurrent CNS risk factors, the Three-Hit model features a therapy-triggered, outside-in cascade with defined temporal checkpoints. The model aims to unify disparate mechanistic findings, explain the enduring nature of cognitive deficits after treatment cessation, and guide stage-specific, mechanism-based precision interventions.

The model delineates three sequential pathological phases. The First Hit (peripheral priming) involves chemotherapy-induced gut dysbiosis and systemic inflammation. The Second Hit (central amplification) entails blood-brain barrier disruption, microglial activation, and oxidative stress-driven synaptic dysfunction. The Third Hit (network consolidation) is defined by epigenetic reprogramming, cellular senescence, and white matter degradation, which collectively solidify chronic cognitive impairment. This staged model may facilitate the design of phase-targeted interventions, including microbiota modulation (First Hit), anti-inflammatory and BBB-stabilizing agents (Second Hit), and senotherapeutics or HDAC6 inhibitors (Third Hit), and may guide neuroprotective strategies toward better-timed application. By linking mechanistic insights to a staged biomarker ecosystem, this review offers a conceptual roadmap for advancing stage-specific therapies for CICN.