RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation

CD47 is a macrophage-specific immune checkpoint protein acting by inhibiting phagocytosis. However, the underlying mechanism maintaining CD47 protein stability in cancer is not clear. Here we show that CD47 undergoes degradation via endocytosis/lysosome pathway. The lysosome protein RAGA interacts with and promotes CD47 lysosome localization and degradation. Disruption of RAGA blocks CD47 degradation, leading to CD47 accumulation, high plasma membrane/intracellular CD47 expression ratio and reduced phagocytic clearance of cancer cells. RAGA deficiency promotes tumor growth due to the accumulation of CD47, which sensitizes the tumor to CD47 blockade. Clinical analysis shows that RAGA and CD47 proteins are negatively correlated in lung adenocarcinoma patient samples. High RAGA protein level is related to longer patient survival. In addition, RAGA^highCD47^low patients show the longest overall survival. Our study thereby not only reveals a mechanism by which RAGA regulates CD47 lysosome degradation, but also suggests RAGA is a potential diagnostic biomarker of lung adenocarcinoma.