The transcription factor thymocyte selection-associated high mobility group box gene (TOX) in tumor-infiltrating CD8+ T cells promotes T cell exhaustion by upregulating the expression of immune checkpoint proteins PD-1, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) [73], T cell immunoglobulin and ITIM domain (TIGIT) [74], and cytotoxic T lymphocyte antigen 4 (CTLA-4), thereby attenuates the outcome of anti-PD-1 therapy (Fig. 1) [75]. The gene discussed is CD8A; the disease is neoplasm.