Publication date: Jul 03, 2025
Polycomb repressive complexes (PRCs) sustain regulatory T (Treg) cell identity through transcriptional silencing, yet their role in modulating Treg functional plasticity during immune adaptation remains unclear. Here, we identify KDM2B, a defining component of non-canonical PRC1. 1, as a critical regulator for sustaining the proportion and immunosuppressive functions of active Treg (aTreg) cells without altering Treg abundance or identity. Mechanistically, PRC1. 1 deposits H2AK119 monoubiquitylation (H2AK119ub1) at active promoters, enabling rather than repressing transcriptional activation of aTreg programs. Disruption of PRC1. 1 via Kdm2b ablation or pharmacological inhibition with iBP, a selective inhibitor, reduces H2AK119ub1, blunts stimulus-dependent transcriptional activation, and suppresses Treg activation. Notably, Treg-specific Kdm2b deletion in melanoma-bearing mice enhances anti-tumor immunity and synergizes with anti-PD-L1 therapy. Therefore, our study underscores H2AK119ub1 as a dual-function epigenetic mark and PRC1. 1 as a molecular rheostat fine-tuning Treg adaptability, establishing PRC1. 1 as a therapeutic target to decouple immune suppression in cancer while preserving Treg homeostasis.
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | melanoma |
| pathway | KEGG | Melanoma |
| disease | MESH | tumor |
| disease | MESH | Melanoma Experimental |