Cytokines orchestrating critical interactions between immune and non-immune cells, such as IL-2, IL-12, and IL-15, have been harnessed [36] and demonstrated the potential to rejuvenate exhausted T cells [37], decrease regulatory T cells (Treg) in the TME, or reprogram macrophage polarization [36], thus enhancing tumor control in synergy with immune checkpoint inhibitors in preclinical models and early-phase clinical trials [38–41]. This evidence concerns the gene IL15 and neoplasm.