*2.4. Chemotherapy and Inflammation*

Cancer therapy may trigger an inflammatory response through several pathways, including direct immune changes in the TME, tumor cell death, and damage to healthy tissue. Associations between symptoms and inflammatory markers such as IL-6, TNF-α, and C-reactive protein (CRP) have been observed for every treatment modality, both in cross-sectional and in longitudinal designs [32]. In patients who recently completed chemotherapy (compared with treatment-naïve patients), Smith et al. [33] observed reduced blood mononuclear cell DNA methylation associated with higher plasma concentrations of sTNFR2 and IL-6. In turn, sTNFR2 was associated with fatigue, suggesting a transient effect of chemotherapy on inflammation and subsequent fatigue. In paclitaxel-treated mice, Loman et al. [34] found increased fatigue and decreased cognitive performance in parallel with reduced microglial immunoreactivity, increased circulating chemokine (CXCL1) expression, as well as a transient increase in brain gene expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and CXCL1 in a brain region-dependent manner. The study implied that the brain-gut-microbiota axis was involved in the neuroinflammation induced by the chemotherapeutic agent.
