In this regard, two major examples are CTLA-4 (cytotoxic T-lymphocyte associated protein 4)—a T-cell co-inhibitory receptor with higher affinity for the same CD28 ligands CD80/CD86 (Lee et al., 1998), and PD-1 (programmed cell death protein 1)—another crucial T-cell co-inhibitory receptor dampening the TCR and CD28 downstream signaling pathways upon engagement with its ligands PD-L1 and PD-L2, which can be expressed by tumor cells and immune cells, including APCs (Figure 2) (Pauken et al., 2021). Here, CD28 is linked to neoplasm.