circADAMTS12 Inhibits the Antitumor Activity of Microglia to Enable Metastatic Colonization in the Brain

Abstract Microglia promote antitumor immunity and suppress breast-to-brain metastasis, which is a lethal complication in patients with breast cancer without effective therapeutic options. Unraveling the molecular mechanism by which breast-to-brain metastasis cancer cells evade microglia-mediated antitumor immunity in the brain could reveal potential treatment strategies. In this study, we showed that gain of expression of the circular RNA circADAMTS12 in cancer cells supported breast cancer metastatic colonization in the brain by suppressing the antitumor activity of microglia. Mechanistically, circADAMTS12 in cancer cells induced anti-inflammatory M2-like polarization of microglia and upregulated PD-L1 expression in both microglia and cancer cells. Furthermore, the elevated PD-L1 in cancer cells inhibited the phagocytic activity of microglia. Both targeting circADAMTS12 and PD-L1 blockade effectively suppressed metastatic brain colonization in T-cell–deficient nude mice, whereas targeting circADAMTS12 synergized with PD-L1 blockade to block brain metastasis in immunocompetent wild-type mice. These findings suggest that circADAMTS12 suppresses microglia-mediated antitumor immunity to support metastatic colonization of breast cancer cells in the brain. Significance: Targeting the circular RNA circADAMTS12 is a potential strategy to circumvent immunosuppression and to inhibit breast cancer brain metastasis development.