Although two 4-1BB agonists have already been used in clinical trials, only recently more insight into the mechanisms by which anti-tumor effect is exerted, is obtained, and it has become clear that at least in preclinical models systemic 4-1BB activation induces a phenotype of CD4+ and CD8+ T cells that is characterized by high expression of the T-box transcription factor Eomes, KLRG1+, and high cytotoxic capacity (125, 127–129). Here, CD4 is linked to neoplasm.