Liquiritin improves macrophage degradation of engulfed tumor cells by promoting the formation of phagolysosomes via NOX2/gp91phox

The incomplete degradation of tumour cells by macrophages (M_φ) is a contributing factor to tumour progression and metastasis, and the degradation function of M_φ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of M_φ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of M_φ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in M_φ phagosomes, causing M_φ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in M_φ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which M_φ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of M_φ to degrade tumour cells by suppressing NOX2.