Angiogenic factors are crucial in the development of human cancers, and the most prominent is VEGF/VEGF receptors (VEGFRs) signaling (Carmeliet and Jain, 2011). VEGFR1 and VEGFR2 have been found to be expressed on tumor cells as well as vascular endothelial cells. The VEGFR1 signaling pathway is essential for tumor development. VEGFR2 is involved in the growth of tumor stem cells. Moreover, VEGF/VEGFR signaling is essential in the formation of the immunosuppressive tumor microenvironment in malignancies (Emmett et al., 2011, Goel and Mercurio, 2013, Dewing et al., 2012).

In addition to the traditional growth factor role of VEGF and VEGFRs, they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis (Li, 2016 #87). VEGF can prevent the function of T cells, increase the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), hinder the maturation and activation of dendritic cells (DCs) and can interact with macrophages and T lymphocytes depending on a certain pathological state (Yang, 2018 #86). Dendritic cells (DCs), macrophages, and lymphocytes further express certain types of VEGFRs (Li, 2016 #87). Given the immunosuppressive role of VEGF, scientists have recently tried to restore the antitumor immunity by targeting VEGF/VEGFR.

Cancer immunotherapy has surpassed surgery, radiation, and chemoradiotherapy as the fourth most popular cancer treatment option. Vaccination utilizes antigen peptides to activate CD8+cytotoxic T lymphocytes (CTLs) in patients (Zahedipour et al., 2021). Both anti-angiogenic treatment and immunotherapy are achieved by VEGFR peptide immunization. This vaccination causes a powerful immune response with memory, which results in the prevention of tumor recurrence. Furthermore, this approach is widely recognized as a simple approach, with high sensitivity, affordable costs, fast synthesis, and a stable and high safety profile (Zahedipour et al., 2021). Peptide vaccination generally involves the use of two primary types of peptides. The first type consists of short peptides that are typically only 9–10 amino acids in length, have a short lifespan, and quickly break down in the serum. They can also be presented directly onto the HLA class I without needing prior processing in professional antigen-presenting cells (APCs). The second type of peptides consists of longer peptides that contain more than 20 amino acids. These peptides are more stable and immunogenic than the short peptides. Dendritic cells have the ability to take up and process epitopes efficiently, which allows them to present them on both class I and class II MHC/HLA molecules. This ability contributes to a powerful and controlled anti-tumor immune response that involves the activation of CD4+ and CD8+ T cells, as well as the production of antibodies by B cells. This response is long-lasting and effective against tumors (Xu et al., 2017 Feb). Furthermore, peptide vaccines can be designed as single peptide, multivalent, and fusion peptides that have been used in various clinical studies.

Clinical trials have been conducted to investigate the use of VEGFRs peptide vaccination in cancer patients, both with and without multiple oncoantigens (Shibao et al., 2018a, Kikuchi et al., 2019). More recently, this vaccination has also been used in patients with progressive neurofibromatosis type 2 (NF2) (Tamura et al., 2019). In this study, researchers found that the number of regulatory T cells expressing Foxp3 decreased after vaccination. This suggests that the cytotoxic T cells generated by the vaccination may be capable of directly killing a range of cells involved in tumor growth, including tumor cells, tumor vessels, and Tregs expressing VEGFR1 and/or VEGFR2. Additionally, the combination of chemotherapy and immunotherapy has been found to be effective due to their synergistic activity (Ramakrishnan and Gabrilovich, 2011). Chemotherapeutic drugs such as gemcitabine, Cisplatin, and Taxanes suppress immunosuppressive T cells, while immunotherapy promotes the proliferation of potential effector immune cells (Miyazawa et al., 2010a). According on these considerations, VEGFR1 and 2 vaccines were utilized in some trials in combination with chemoradiotherapy (Stupp and Mason, 2005). The histopathological findings showed that VEGFR1 and 2 peptide vaccination can target a broad range of cells associated with tumor growth, including vascular endothelial cells, tumor cells, and Foxp3+ Tregs expressing VEGFR1 and/or VEGFR2. This finding supports the rationale for combining VEGFRs peptide vaccination with chemotherapy. Studies have also suggested that VEGFR2-targeting treatment may have the potential to selectively kill Tregs because these cells express VEGFR2 and can be targeted by this treatment. The presence of cleaved caspase 3 further supports these findings (Suzuki et al., 2010, Terme et al., 2013). Clinical trials have been conducted using VEGFR-derived epitopes in patients with various types of cancer, such as advanced gastrointestinal and renal cell cancers. These trials demonstrated that the treatment was safe and well-tolerated by the patients (Hazama et al., 2014a, Tamura et al., 2020, Masuzawa et al., 2012a, Wada et al., 2005). However, there is no systematic review to provide a comprehensive evaluation of efficacy and tolerability of VEGF/VEGFR peptide vaccines. Thus, our objective was to perform a systematic review to elucidate the results of the clinical trials using peptide vaccines targeting VEGF/VEGFR, which includes effectiveness in treating the disease, survival rate, and any potential side effects.