(A–B) Gpr132 knockdown decreased Gpr132 mRNA (A) and protein (B) in macrophages (n = 3). (C) In co-cultures, Gpr132 knockdown in macrophages reduced cancer cell growth (n = 3). (D–E) Gpr132 over-expression increased both mRNA (D) and protein (E) in macrophages (n = 3). (F) In co-cultures, Gpr132 over-expression in macrophages enhanced cancer cell growth (n = 3). Cancer cell alone without macrophages (no mf) served as a negative control. (G) Gpr132-KO macrophages exhibited lower expression of pro-inflammatory genes compared with WT controls (n = 3). (H) Gpr132-KO macrophages displayed higher levels of pro-apoptotic genes and lower levels of anti-apoptotic genes (n = 3). (I–J) In vitro co-cultures showed that Gpr132 deletion in macrophages significantly reduced the ability of macrophages to promote cancer cell colony formation (I) and proliferation (J) (n = 3). (K) In vivo mammary fat pad tumor grafts showed that tumor growth was significantly diminished in Gpr132-KO mice compared with WT or Gpr132-Het mice (n = 6). (L) In in vitro co-cultures, Rosi pre-treated WT macrophages but not Rosi pre-treated Gpr132-KO macrophages were able to inhibit cancer cell growth (n = 3). (M) The ability of Rosi to suppress tumor growth in vivo was abolished in Gpr132-KO mice (n = 6). Four days after EO771 cell mammary fat pad injection, Gpr132-KO or WT mice were treated with Veh or Rosi (10 mg/kg) every two days. (N) The ability of macrophage PPARγ deletion to exacerbate tumor growth in vivo was abolished in Gpr132-KO mice (n = 4). DKO, mf-g/Gpr132 double KO. (O–P) Pharmacological Gpr132 inhibition impeded mammary tumor growth. Female mice (six-week-old) were treated with si-Gpr132 (n = 8) or si-Ctrl (n = 6) for 18 days via intravenous injection at 10 μg/mouse twice/week, three days before and 15 days after EO771 cell mammary fat pad injection. (O) Tumor volume was significantly decreased by si-Gpr132 treatment. (P) Gpr132 expression in tumors was effectively depleted. Error bars, SD; *p<0.05; **p<0.01; ***p<0.005; ****p<0.001; n.s. non-significant. (Q) A simplified working model for how macrophage PPARγ inhibits inflammation and tumor growth by repressing the transcription of macrophage Gpr132, a novel pro-inflammatory and pro-tumor membrane receptor. Upon sensing and activation by tumor signals, macrophage Gpr132 may modulate macrophage intracellular signaling and downstream targets, which in turn promotes cancer cell proliferation (indicated by the dashed line). Macrophage PPARγ deficiency increases Gpr132 level to afford better tumor sensing by macrophages, thereby promoting tumor growth. Pharmacological Gpr132 inhibition via either PPARγ agonist or Gpr132 blockade attenuates breast cancer progression. Moreover, both macrophage PPARγ and Gpr132 are key mediators of the anti-tumor effects of the clinically used TZD drug rosiglitazone.