Low-dose apatinib optimizes the vascular normalization and enhances the antitumor effect of PD-1 inhibitor in gastric cancer.

Background: Apatinib is a tyrosine kinase inhibitor that has shown potential in combination with immune checkpoint inhibitors (ICIs) in gastric cancer (GC); however, its role in GC is unclear. This research aims to investigate the effect of low-dose apatinib in GC, and analyze the mechanisms of its underlying action. Methods: A mouse model of GC was established, and the experimental mice were divided into different groups for different treatment: group NS (normal saline), group A (low-dose apatinib 50 mg/kg), group B (high-dose apatinib 200 mg/kg), group C [programmed cell death protein 1 (PD-1) inhibitor monotherapy], and group D (PD-1 inhibitor combined with low-dose apatinib). After 14 days of treatment, the tumor and blood samples were collected from all mice for histological and cytokine detection. Results: Compared with the control group, mice in the low-dose apatinib group showed smaller tumor volumes and slower growth. CD31/α-smooth muscle actin (α-SMA) double staining revealed significantly higher coverage of perivascular cells in the low-dose apatinib group by contrast to the control and high-dose apatinib groups, suggesting that low-dose apatinib may alleviate hypoxia. Compared to the high-dose apatinib group, the expression of hypoxia inducible factor 1 alpha (HIF1α) significantly decreased in the low-dose apatinib group. Hematoxylin and eosin (HE) staining results showed a higher proportion of necrotic tumor tissues in the group of mice treated with low-dose apatinib combined with PD-1 inhibitor than in other groups. In addition, this combined treatment significantly reduced the expression of NG2 and HIF1α in mouse tumor tissues, indicating a more normalized vascular density, and also increased the proportion of CD8 Conclusions: Low-dose apatinib enhances the antitumor effect of PD-1 inhibitor by normalizing tumor-related blood vessels, alleviating intratumor hypoxia and altering immunosuppressive microenvironment (IM).