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Targeting isoQC in cancer immunotherapy. The interaction between CD47 on erythrocyte and SIRPα on macrophages triggers a “don’t eat me” signal, thus the erythrocyte is not engulfed by macrophages. (b) Interrupting the CD47-SIRPα pathway either by blocking CD47 or SIRPα lead to the phagocytosis of erythrocytes by macrophages. (c) The interaction between CD47 on tumor cells and SIRPα on macrophages triggers a “don’t eat me” signal, thus the tumor cells are not engulfed by macrophages, by this mechanism, tumor cells realize their immune surveillance evasion. The pyroglutamylation of CD47 is critical for the binding between CD47 and SIRPα. (d) Blocking the CD47-SIRPα pathway leads to the phagocytosis of tumor cells by macrophages but meanwhile brings the adverse effect that the erythrocytes are phagocytized by the macrophages. Targeting isoQC by SEN177 or other inhibitors inhibits the pyroglutamylation of CD47 and thus blocks the interaction between CD47 and SIRPα. IsoQC is a Golgi-resident enzyme that is not expressed on erythrocytes, thus the erythrocytes would not be affected by targeting isoQC.

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