CD4 and neoplasm: T-cell exhaustion was a term first coined in the context of chronic viral infection, as a state of dysfunctional phenotype where T cells progressively lose their effector function due to chronic antigen exposure, further promoted by a lack of CD4+ T-cell help and exposure to immunosuppressive cytokines.22,142 This concept expanded to the field of cancer research due to high tumor-antigen loads and the tolerogenic TME.