CD96 is an immune checkpoint receptor that is primarily expressed on various types of T cells and natural killer (NK) cells. It is involved in the regulation of immune responses, and its expression has been correlated with immune profile and clinical outcomes in cancers such as glioma. CD96 can act as both a co-stimulatory and co-inhibitory receptor, which adds to its complex role in immune regulation. In the context of cancer immunotherapy, CD96 has gained attention for its potential as a therapeutic target. It is part of the immunoglobulin superfamily and interacts with nectin and nectin-like proteins. Similar to the CD28/CTLA-4 pathway, CD96 and TIGIT act as co-inhibitory receptors alongside the co-stimulatory receptor CD226. This suggests that targeting CD96 could enhance T-cell function against human cancer and infectious disease. CD96 expression has been shown to be higher in mesenchymal-molecular subtype glioma, and it is significantly linked to immune functions within these tumors. Moreover, higher CD96 expression in gliomas is associated with more immune cells infiltration, indicating its role in immune responses within the tumor microenvironment. In terms of its immune functions, CD96 is involved in the regulation of T cells, leukocyte regulation, leukocyte cell–cell adhesion, the MHC protein complex, and MHC class II proteins. It is also linked to inflammatory activities and is associated with the expression of other immune checkpoint markers such as PD-L1, CTLA-4, TIM-3, and STAT3, indicating potential synergistic effects in immunotherapy.