Kallistatin enhances the phagocytic function of macrophages by decreasing the expression of CD24 in gastric cancer cells via the HIF-1α signaling pathway

Abstract Gastric cancer, the most frequently diagnosed type of primary cancers, is associated with a high mortality rate, and imposes a significant burden on patients and society. Recent studies have found that the kallikrein-binding protein kallistatin (KS) is involved in cancer progression. However, the effects of KS on macrophages in the immune microenvironment of gastric cancer remains elusive. In the present study, we found that overexpression of KS could enhance macrophages to engulf gastric cells in vitro. We also identified that, through immunohistochemical analysis, there was an increase in CD24 expression in gastric cancer, which was associated with unfavorable prognoses. Next, it was revealed that KS overexpression could downregulate the expression of CD24 by Sanger sequencing. In vitro experiments revealed that KS overexpression resulted in the inhibition of the hypoxia-inducible factor (HIF)-1α signaling pathway, as well as decreased expression of CD24. HIF-1α downregulation also decreased the transcription and expression of CD24 in vitro, with a magnitude similar to that seen upon KS overexpression. Furthermore, activation of AKT-HIF-1α reversed the inhibitory effect of KS overexpression, restoring the transcription and expression of CD24. Collectively, KS decreases CD24 expression via the AKT-HIF-1α pathway, altering the anti-phagocytic pattern of gastric cancer cells towards tumor-associated macrophages and strengthening innate immunity, thereby influencing the prognosis of gastric cancer. In summary, our findings have identified KS as a novel factor in the pathway that reduces CD24 expression, thus contributing to a deeper understanding of the mechanisms involved in tumor immune evasion and supplying a potential drug for gastric cancer immunotherapy.