B7-H5, also known as VISTA (V-domain immunoglobulin suppressor of T cell activation), is one of the negative immune checkpoints of the B7 family, which was first discovered in 2011. VISTA is a well-defined type I immunoglobulin membrane protein with 279 amino acids, including cytoplasmic tail (96 amino acid residues), transmembrane domain (TMD) (21 amino acid residues), and extracellular domain (162 amino acid residues). The encoding gene of VISTA is Vsir, which is not only situated on chromosome 10 at a distant position from all members of the immunoglobulin superfamily but also is located within the intron of the CDH23 gene. VISTA remarkably has a high level of conservation among members of the B7 family and represents 76 percent homology between humans and mice. VISTA participates in the controlling of immune system reactions due to possessing the main homeostatic role. VISTA is mainly expressed in myeloid cells such as macrophages, monocytes, dendritic cells, and T cells, and VISTA is highly expressed in a variety of tumors, including melanoma, pancreatic cancer, prostate cancer, non-small cell lung cancer, renal cell carcinoma, and CRC. VISTA, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. Importantly, the expression of VISTA has been associated with the prognosis of patients with CRC. Isabelle et al. utilized a VISTA-specific blocking mAb to demonstrate that VISTA blockade enhanced protective antitumor immunity and impaired the suppressive character of the tumor microenvironment (TME). In acute myeloid leukemia, myeloid-derived suppressor cells (MDSCs)-expressed  VISTA significantly caused the inhibition of CD8+ T-cell activity. These findings indicated that B7-H5 is an important negative checkpoint regulator in the TME, but the clinical significance of the VISTA expression in CRC and the role of VISTA in the TME remain to be elucidated.