Blood IL-1α and IL-6 predict specific breast cancer-induced increases in hippocampal pro-inflammatory cytokines in mice

Neuroinflammation is a key factor in cognitive and behavioral changes seen in patients with non-CNS cancers, and cytokine levels in the blood are often used as a proxy for brain inflammation. However, this approach has yielded inconsistent results, and a common inflammatory signature remains elusive. To explore whether a blood-to-brain inflammatory signature exists across breast cancer types, we assessed cytokine and glial protein responses in the hippocampus, prefrontal cortex (PFC), and their relationship to serum cytokines in mice bearing three different mammary cancers (n = 40). While cytokine profiles in both serum and brain varied by cancer type, IL-1β and IL-4 were consistently altered across brain regions. In some cases, elevated serum IL-1α and IL-6 correlated with increased hippocampal IL-6. These findings support the use of blood cytokines to identify cancer patients at risk for cognitive and psychiatric comorbidities. However, our data also suggest that relying solely on serum cytokines may lead to under-diagnosis, as some mice exhibited brain cytokine elevations without changes in serum levels. This underscores the need for a broader range of inflammatory markers in blood to better identify at-risk patients. Brain region-specific differences in the cytokine response to mammary cancer highlighted the hippocampus as more vulnerable to cancer-induced inflammation than the PFC. We observed region-specific glial cell reactivity, however, only astrocyte and oligodendrocyte markers were correlated with cytokine changes within the hippocampus. Elevated serum IL-1α and IL-6 were correlated with reduced cortical astrocyte reactivity, suggesting that these cytokines can inform glial cell-specific changes in this region.