Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPAR gamma loss-of-function mutations, but inhibited by PPAR gamma agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPAR gamma tumor-suppressive functions. Here we report that macrophage PPAR gamma deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPAR gamma target in macrophage whose expression is enhanced by PPAR gamma loss but repressed by PPAR gamma activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPAR gamma and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPAR gamma and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects.