Targeting IKZF2 with molecular glue degraders for cancer immunotherapy.

Authors

Yaoguang Huang, Shuoqi Huang, Wenwu Liu

Published in

Drug discovery today. Pages 104820. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

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.

PMID:
42833391
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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