Leveraging the synergy between anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers

Abstract

The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors.

Keywords: anti-angiogenic therapy; digestive system cancer; immune checkpoint blockade; immunotherapy; tumor microenvironment; vessel normalization.

Figure 1

VEGF and angiogenesis.

Figure 2

Regulation of tumor angiogenesis by different immune cells. mDCs and M1-type TAMs release IFN-α, IL-12, and other cytokines, alongside chemokines like CXCL9 and CXCL10, to inhibit angiogenesis. CD8⁺T cells and TH1 cells additionally secrete IFN-γ, which suppresses angiogenesis and promotes vascular normalization. Conversely, iDCs, MDSCs, M2-type TAMs, and TEM cells promote angiogenesis through factors like VEGF and IL-10, while Tregs, TH2, and TH17 cells contribute by releasing VEGF and IL-4. Immune cells further regulate angiogenesis through interactions. For instance, mDCs and TH1 cells can polarize macrophages toward the M1 type, whereas MDSCs and Tregs reprogram TAMs toward the M2 type. Some MDSCs can even differentiate into endothelial-like cells and incorporate into the tumor vasculature.

Figure 3

Mechanisms of angiogenesis in tumors. (A) Sprouting angiogenesis, during which a new vessel branches from an existing vessel. The key biological process involves the balance between the formation of “tip” and “stalk” endothelial cells. (B) Vasculogenesis, during which new blood vessels are generated by endothelial progenitor cells to form networks without the presence of pre-existing vessels. (C) Intussusceptive angiogenesis, which involves the formation of a double lumen and the split of an existing vessel into two new functional blood vessels. (D) Vascular mimicry. Tumor cells form vessel-like structures independently of endothelial cells to facilitate blood flow. (E) Vessel co-option. Tumor cells utilize existing blood vessels for their blood supply. (F) Transdifferentiation. Certain cancer stem cells differentiate into endothelial-like cells and integrate into the vascular structure to support the tumor’s blood supply. RBCs, red blood cells; ECs, endothelial cells; CSCs, cancer stem cells.