Targeting IKZF2 with molecular glue degraders for cancer immunotherapy

Regulatory T cells (Tregs) restrain antitumor immunity and limit responses to immune checkpoint blockade (ICB). IKZF2 (Helios), a zinc-finger transcription factor enriched in Tregs, sustains suppressive programs under inflammatory conditions. Therefore, selective IKZF2 degradation has emerged as a strategy to reprogram intratumoral Tregs and enhance antitumor immunity. In this review, we summarize the biological rationale for IKZF2 targeting, the structural basis of cereblon (CRBN)-mediated IKZF2 recruitment and medicinal chemistry principles for improving neosubstrate selectivity. We highlight how degron recognition, CRBN surface remodelling and ternary-complex geometry shape potency, selectivity, off-target liability and translational opportunities for rational immunotherapy combinations.