To clarify the modulation of γδ T cells’ effector functions solely by cytokines, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells and demonstrate that IL-12 and IL-18 when combined, so-called bypass stimulation, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. The gene discussed is IFNG; the disease is neoplasm.