Circadian rhythms of macrophages are altered by the acidic tumor microenvironment

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms. Synopsis Circadian rhythms of macrophages are altered by conditions associated with the tumor microenvironment, including acidic pH. This may be responsible for the heterogeneity in circadian clock gene expression within the tumor-associated macrophage population. Circadian rhythms of macrophages are altered by polarizing stimuli, acidic pH, and lactate. There is circadian disorder in the tumor-associated macrophage population. Heterogeneity of circadian rhythms and circadian gene expression within a population may underlie circadian disorder. The circadian clock in tumor-associated macrophages plays a tumor-suppressive role in pancreatic cancer. Circadian rhythms of macrophages are altered by conditions associated with the tumor microenvironment, including acidic pH. This may be responsible for the heterogeneity in circadian clock gene expression within the tumor-associated macrophage population.