The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages

Significance Expression and function of odorant receptors (ORs) are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Here, we hypothesized that the macrophage OR Olfr78 functions as a tumor-derived lactate sensor and shapes the macrophage–tumor axis. Olfr78 and the G protein–coupled receptor Gpr132 form a heterodimer that senses lactate in the tumor microenvironment, leading to generation of tumor-associated macrophages with a protumoral M2 phenotype, which promotes tumor progression and metastasis. Our findings suggest an alternative strategy for cancer treatment, namely targeting the interaction between tumor-derived metabolites and ORs.