Inhibition of Skp2 enhances anti-tumor immunity of macrophages by regulating CD47 in gastric cancer

S-phase kinase-associated protein 2 (Skp2), a member of the ubiquitin E3 ligase F-box family, has been confirmed to control the tumorigenesis and progression of varieties of tumors, and is a potential pharmacological target for anticancer therapy. Recent research reveal that Skp2 affects tumor immune microenvironment through regulating immune checkpoints. However, the effect of Skp2 on the tumor microenvironment (TME) and its underlying regulatory mechanism in gastric cancer is still unclear. This study was aim to investigate the role of Skp2 in gastric cancer immunotherapy. Through database and experimental analysis, it was found that inhibition of Skp2 could reduce the expression of tumor immune checkpoint CD47. Co-culture experiments in vitro showed that inhibition of Skp2 could enhance the phagocytosis of macrophages on gastric cancer cells. Further studies showed that Skp2 affected the expression of the lysosomal protein RAGA and regulated the degradation of CD47 lysosomes. Subsequently, a gastric cancer SNU601 xenograft model also showed that inhibition of Skp2 downregulated CD47 levels in vivo. Small inhibitor of Skp2 combined with 5-FU chemotherapy could synergistically inhibit tumor growth, which affected the changes of immune microenvironment and regulated the infiltration of macrophages. To sum up, this study confirmed that Skp2 as an important regulator of phagocytosis and provided a new theoretical basis for improving anti-tumor immune efficacy and related drug development.