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Tumours can evade immune system attack through the recruitment of immune-suppressive FOXP3+ regulatory T (Treg) cells, which can limit the activation and expansion of tumour-specific effector T (Teff) cells. Recently, the Ikaros transcription factor family member IKZF2 (Helios) — which plays a crucial role in maintaining the function and stability of Treg cells — has emerged as an attractive target for enhancing the antitumour immune response. However, targeting zinc finger transcription factors such as IKZF2 is challenging, as they are mostly unstructured and lack ligandable sites. Now, Bonazzi et al. describe the development of NVP-DKY709, a first-in-class selective cereblon (CRBN) glue degrader of IKZF2, which spares IKZF1 and IKZF3 from degradation. Solving the X-ray crystal structure of IKZF2 zinc fingers bound to DDB1:CRBN:NVP-DKY709 explained the target selectivity of NVP-DKY709. In vitro, NVP-DKY709 modulated Treg cell and Teff cell functions. In a mouse breast cancer xenograft model, daily oral dosing with NVP-DKY709 led to degradation of IKZF2 in tumour and peripheral blood Treg cells, reducing tumour growth similarly to that achieved with the anti-PD1 antibody PDR001. Oral NVP-DKY709 effectively degraded IKZF2 in monkeys and patients and is currently being evaluated in a first-in-human phase I trial in solid tumours.