ICOS and cancer: Among these cells, Tregs play a highlighted role in cancer ignorance, cancer immunologic tolerance and cancer poor prognosis by (a) secretion of immunosuppressive agents including TGF-β, IL-10, and IL-35, (b) Perforin/Granzyme-mediated direct cytotoxicity, (c) metabolic interruption by consumption of IL-2 and making IL-2 deprivation in TME, cAMP- and A2 adenosine receptor-mediated immunosuppression, (d) dendritic cells (DCs) suppression by cell-cell interaction, and (e) inhibitory receptors and immune checkpoints including IDO, ICOS, CTLA-4, TIM-3, LAG-3, PD-1, and TIGIT (15).