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The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6C lo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6C neg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Influenza A virus (IAV) infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV infection has remained unidentified. Here, we show that HA binds to the voltage-dependent Ca 2+ channel Ca v 1.2 to trigger intracellular Ca 2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca 2+ channel blockers (CCBs) or by knockdown of Ca v 1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Ca v 1.2 restored Ca 2+ oscillations and virus infection in Ca v 1.2-depleted cells, demonstrating the significance of Ca v 1.2 sialylation. Taken together, we identify Ca v 1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry., (Copyright © 2018 Elsevier Inc. All rights reserved.)