The rapid development of
tumor immunotherapy has improved the management of patients with
cancer. However, several key problems of
tumor immunotherapy, including the insufficient activation of effector T cells, poor
tumor invasion, and poor immune killing ability, lead to a low response rate. In the present study, a synergistic strategy was developed by combining in situ
tumor vaccines, gene-mediated downregulation of
tumor angiogenesis, and anti-PD-L1
therapy. In situ
tumor vaccines and antitumor angiogenesis were achieved by codelivering unmethylated
cytosine-
phosphate-
guanine (CpG) and
vascular endothelial growth factor (
VEGF)-silencing gene (shVEGF) via a
hyaluronic acid (HA)-modified HA/PEI/shVEGF/CpG system. Necrotic
tumor cells and CpG adjuvants formed in situ
tumor vaccines and activated the host immune response. Moreover,
VEGF silencing reduced
tumor angiogenesis and prompted the homogeneous distribution of
tumor blood vessels to facilitate immune cell infiltration. Meanwhile, anti-angiogenesis also improved the immunosuppressive tumor microenvironment. To further improve the specific
tumor-killing effect, an anti-PD-L1 antibody was introduced for
immune checkpoint blockade, thereby boosting antitumor immune responses. The combination
therapy strategy presented in the present study could act in the multiple stages of the
tumor immunotherapy cycle, which is expected to offer a new avenue for clinical
tumor immunotherapy.