Cancer immunotherapy, especially immune checkpoint blockade (ICB), has revolutionized oncology. However, only a limited number of patients benefit from immunotherapy, and some cancers that initially respond to immunotherapy will eventually relapse and progress. Therefore, some studies have investigated the combination of immunotherapy with other therapies to overcome resistance to monotherapy. Recently, several preclinical and clinical studies have shown that the tumor vasculature is the determinant of whether immunotherapy triggers an antitumor response. Therefore, vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes. Successful antitumor immune response requires a complete “cancer-immune cycle”, including t                                                                                                                                                                              �

Angiogenesis inducers, especially vascular endothelial growth factor (vegf), can interfere with the activation, infiltration and function of T cells, thereby breaking the "cancer-immune circulation". Together with tumor vascular remodeling regulated by immunostimulation, vegf-mediated immunosuppression provides a solid therapeutic basis for the treatment of solid tumors with combined immunotherapy and antiangiogenic drugs. With the success of the recent landmark phase clinical trial, the combination of immune checkpoint inhibitors (ici) and antiangiogenic drugs has become the first-line treatment for a variety of solid tumors, and the efficacy of such combinations in other solid tumors remains to be verified by ongoing research.

In this review, the synergistic effects between anti-angiogenic drugs and cancer immunotherapy are discussed based on the results of preclinical and translational studies. Then, the latest advances in randomized clinical trials are discussed. Due to recent success, the combination of inclusion of ici    was the focus of this review, but combinations containing other immunotherapies are also discussed. Finally, we attempt to define the key challenges of using ici     in combination with anti-angiogenic drugs to promote coordination and collaboration within the research community.

Immune checkpoints are evolutionarily conserved molecules, including but not limited to programmed cell death proteins 1                                                                                                                                                                                                                                                 

,monocytes and specific dendritic cells (DC). In addition to tumor cells, pd-l1     is also expressed on a variety of cells in the tumor microenvironment (TM), such as                                                                                                                                                                                                                                   

Immune checkpoint inhibitors (ICIs) are designed to block immune checkpoints to "release" powerful t-cell anti-tumor responses. Over the past decade, the use of nivolumab and pembrolizumab (both anti-pd-1 monoclonal antibodies) and others has revolutionized the treatment of a variety of solid tumors by prolonging survival in patients with refractory tumors. To date, 10 types of ici for the pd-1/pd-l1 signaling pathways have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of 19 different types of cancers, including tissue agnostic indications.

Although unprecedented persistent response rates were observed using ici, primary drug resistance (cancer did not respond to ici) and acquired drug resistance (cancer initially responded to ici, but eventually relapse and progress) prevented most patients from benefiting from treatment. According to a survey, it was estimated that up to 87% of eligible patients did not respond to ici, FDA approved. In some clinical trials, some common cancer types (advanced stage)

Breast cancer, prostate cancer and liver cancer) respond to icis less frequently. Ici   A key reason for drug resistance is tumor manipulation of alternative immunosuppressive mechanisms to avoid immune clearance. To overcome the resistance of monotherapy, some researchers have studied the combination of immunotherapy with other therapies. The transition from monotherapy to combination therapy is significant, with 3674    80% of ongoing clinical trials testing a combination of pd-1/pd-l1 signaling pathway inhibitors tested.

In 1971, judah folkman proposed the concept of "antiangiogenesis", that is, to prevent angiogenesis for clinical benefit. Bevacizumab is an anti-vegf monoclonal antibody. After a landmark phase clinical trial was successful, it was approved in 2004. FDA                                                                                                                                                                                                                        

These drugs can be divided into two categories: protein inhibitors and multi-target receptor tyrosine kinase inhibitors (tkis). Although effective antiangiogenic treatments have a well-known effect in preventing tumor growth, in some cases, they cannot eradicate tumors through monotherapy due to compensatory mechanisms. Therefore, combining antiangiogenic agents with other therapeutic strategies may be necessary to effectively eradicate tumors; among these strategies, targeting vegf/vegfr axis has become the most common combination therapy method in 2020

By binding to multiple immune cells and receptors on endothelial cells, vegf interferes with the entire cancer immune cycle—from the initiation of anti-cancer immunity to the recruitment of t                                                                                                                                                                                                                                      �

A powerful anti-cancer immune response relies on effective cancer neoantigen presentation to initiate and activate naive cells.

The loss of cancer neoantigen presentation and tumor specificity        The deletion of cells is the main factor leading to cancer immunotherapy resistance. t     The successful initiation and activation of cells is affected by two independent factors: the function of antigen presenting cells and the availability of initial t        The availability of cells. nndcs                                                                                                                                                                                                     �

Later, they will move to the tumor drainage lymph nodes and present the antigen captured on the MHCI molecule to the cd8 t cells, thereby triggering and activating antigen-specific initial t cells. At the same time, immature dcs are gradually matured, characterized by upregulation of co-stimulatory molecules expression and increasing secretion of proinflammatory cytokines. One of the earliest reported immunosuppressive functions of antiangiogenic factors is the tumor-derived vegf inhibiting the maturation of progenitor cells, which leads to the reduction of presentation of cancer neoantigens in the tumor drainage lymph nodes, thus helping the tumor escape from the epidemic.

Compared with matured                                                                                                                                                                                                                                                             �

Metastatic malignant tumors. In addition, it has been reported that VEGF upregulates the expression of pd-l1 on the bone marrow dc, which may impair the DC-mediated t-cell initiation and proliferation. In vitro studies have shown that the function of differentiated in the presence of VEGF can be restored by inhibiting the VEGF axis by bevacizumab or sorafenib. Therefore, the administration of anti-angiogenesis inhibitors increases the functionality necessary for cell initiation and activation of t-cells in lymph nodes.

2. Antiangiogenesis treatment promotes effector cell infiltration

Immune cells require a normal and functional tumor vascular network to infiltrate tumors. Effective transport of tumor-specific cells to tumor sites and infiltrate them into the tumor bed is necessary for response to cancer immunotherapy. Therefore, poor cell infiltration in tumors before treatment is often associated with resistance to cancer immunotherapy. The "angiogenesis switch" is controlled by anti-angiogenesis inducers and inhibitors, respectively, such as vegf and thrombocytopen-1. The hypoxic microenvironment in solid tumors leads to the continuous production of angiogenesis factors; therefore, the "angiogenesis switch" is constantly activated to meet oxygen and nutritional needs. As a result, the newly generated blood vessels are immature and abnormal and impaired T cell extravasation.

One potential explanation for cell rejection is the downregulation of chemokines secreted by endothelial cells, such as cxcl10 and cxcl11. Another reason why effector cells cannot penetrate solid tumors may be the downregulation of adhesion molecules in dysfunctional tumor endothelium. T cell infiltration relies on adhesion molecules, such as intracellular adhesion molecule 1 (icam1), vascular adhesion molecule 1 (vcam1) and cd34. In vivo studies have shown that vegf impairs leukocyte-vascular wall interaction; this mechanism involves veg

F-induced tumor necrosis factor α (TNF-α) mediated downregulation of on-endothelial expression of ICAM1 and VCAM1. In human cancer, the expression of CD34 in endothelial cells is also downregulated by VCAM. In CRC and melanoma mouse models, antiangiogenic drug treatment promotes leukocyte-vascular wall interaction by increasing the expression of adhesion molecules ICAM-1 and VCAM-1, thereby increasing leukocyte infiltration. In short, VEGF induced dysfunctional tumor vascular system will interfere with t                                                                                                                                                                                    �

3. Antiangiogenic therapy reduces immunosuppression

Preclinical studies have shown that vegf promotes depletion by upregulating the production of multiple immune checkpoint molecules, including pd-1, ctla-4, lag3, tim3. In other preclinical studies, it has been reported that vegf inhibits their function by inhibiting the proliferation and cytotoxic function of ctl. In crc mice

In the model, anti-vegf treatment reversed the expression of inhibitory molecules related to t                                                                                                                                                                                                                                                    �

In contrast to the inhibitory effect t                                                                                                                                                                                                                                                           

mdscs     is a mature immunosuppressive cell, Vegf promotes the amplification of mdscs, whose mechanism involves signal transduction and activation of transcriptional activator 3 (stat3). Consistent with this finding, preclinical studies have shown that bevacizumab reduces the number of mdsc                                                                                                                                                                                                                 

Abnormal tumor blood vessels will reduce blood flow, affect the delivery of therapeutic drugs, worsen hypoxia, and interfere with the recruitment of immune cells (especially cd8 t                                                                                                                                                                                                                                        

It is claimed that wise use of antiangiogenic drugs can normalize tumor blood vessels and improve their function. Although the vascular normalization response reduces immunosuppression, little is known about its regulation. In 2017, Tian et al. reported that icis can lead to the remodeling of the tumor vascular system. In their study, pd-1 and ctla-4 blockers improved vascular perfusion, reduced tumor blood vessel density, and relieved hypoxia in tme. These are signs of tumor vascular normalization.

To date, the exact role of effect                                                                                                                                                                                                                                                           �

Preclinical studies assessing the combination of cancer immunotherapy and anti-angiogenic drugs showed promising results. For example, in a mouse model of colon cancer, anti-pd-1                                                                                                                                                                                                                                         

In the mutual regulation between cancer immunotherapy, we propose an immune stimulation of vascular regulation circulation to explain the synergistic effect between anti-angiogenic drugs and cancer immunotherapy. On the one hand, anti-angiogenic agents promote vascular remodeling and alleviate immunosuppression in tme. Normalized vascular promotes the infiltration of immune cells and improves their function, leading to tumor regression. On the other hand, immunotherapy activates effector t                                                                                                                                                                                                     �
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