Chemobrain as a Neuroimmune Syndrome: Mechanisms, Modifiers, and Emerging Multi-Target Therapeutic Strategies

Chemotherapy-induced cognitive impairment (CICI), often referred to as "chemobrain," is a common and sometimes persistent consequence of cancer treatment, characterized by deficits in memory, attention, executive function, and processing speed; it disproportionately affects older adults and women, suggesting a role for aging- and sex-related biological factors, including estrogen depletion. This work examines the potential of dietary phenolic compounds as multi-target modulators of mechanisms underlying CICI. A narrative synthesis of preclinical and clinical evidence was conducted, focusing on major phenolic subclasses (flavonoids, phenolic acids, stilbenes, lignans, and secoiridoids) and their effects on pathways implicated in chemotherapy-related neurotoxicity. The reviewed data indicate that phenolic compounds can influence redox balance, neuroinflammatory responses, mitochondrial function, synaptic plasticity, and estrogen-related signaling, with effects that appear to be structure-dependent; however, evidence remains heterogeneous and largely derived from experimental models rather than studies in humans. Overall, the current findings suggest that selected phenolic compounds could mitigate vulnerability to CICI, particularly in higher risk groups such as older individuals and women with low estrogen levels. These compounds represent promising and safe adjunctive strategies, although further well-designed clinical studies are needed to confirm their efficacy and clarify the underlying mechanisms.