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The clinical application of immunostimulatory cytokines to treat cancer has been limited by severe toxicities resulting from systemic administration. Although the interleukin 2 (IL-2) mimetic Neoleukin-2/15 (Neo-2/15) induces potent immunotherapeutic effects with reduced toxicity when compared with natural IL-2 (by avoiding activation of CD25+ immune cells), on-target, off-tumour activation of immune cells could still lead to toxicity at high doses. To circumvent this, Quijano-Rubio et al. report the design of a two-component split version of Neo-2/15, which is only active upon colocalization of the two components at the site of the tumour. In syngeneic mouse melanoma models, engineering the split Neo-2/15 to target specific tumour antigens led to complete remission and attenuated toxicity compared with systemic intact Neo-2/15 treatment. Similarly, when engineered to target specific immune cells, the split-Neo-2/15 selectively expanded CD8+ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell proliferation in a lymphoma xenograft model, enhancing antitumour efficacy and survival.