The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung
tumors gain constitutive NRF2 activity which contributes to
cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote
cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator
CDDO-Methyl ester (
CDDO-Me or
bardoxolone methyl) reprogrammed Nrf2 wild-type (WT)
tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a
tumor-promoting to a
tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα,
IL-6, and MHC-II and a decrease in the
tumor-promoting factors
VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs.
CDDO-Me decreased
tumor burden (p < 0.001) and improved pathological grade (p < 0.05) in WT but not Nrf2 KO A/J mice.
Tumor burden in Nrf2 KO mice was 4.6-fold higher (p < 0.001) than in WT mice, irrespective of treatment.
CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (p < 0.0001). In summary, Nrf2 KO exacerbates lung
tumorigenesis in A/J mice, and
CDDO-Me promotes an Nrf2-dependent, anti-
cancer macrophage phenotype.