Lactate and TGF-β antagonistically regulate inflammasome activation in the tumor microenvironment.

The tumor microenvironment significantly affects tumor progression, and tumor cells can also remodel the tumor microenvironment through complex interaction. Inflammasomes are innate immune system receptors/sensors that regulate an inflammatory response mainly mediated by the nucleotide-binding oligomerization domain-like receptors in macrophages, which can also influence the formation, progression and therapeutic response of cancer. However, the effects of tumor-derived factors in the microenvironment on inflammasomes have rarely been reported. In this study, we found that lactate, as the main metabolite of tumor cells could specifically activate the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 inflammasome through increasing the level of reactive oxygen species (ROS) in THP-1-derived macrophages. Furthermore, we showed that transforming growth factor-β (TGF-β), a cytokine accumulated in the tumor microenvironment, could be induced by lactate treatment in tumor cells, and in turn inhibit inflammasome activation induced by lactate and other canonical ligands in macrophages. In addition, TGF-β might induce autophagy of macrophages in a SMAD-dependent manner, leading to ROS clearance and eventually inhibiting the activation of inflammasomes. Collectively, these results indicated that in the tumor microenvironment, tumor-derived lactate could act as a danger signal alerting innate immunity, but nevertheless tumor cells produced more TGF-β to avoid immune surveillance.