ZBTB21 Is a Dual Suppressor of Pyroptosis and MHC‐I Antigen Presentation That Promotes Tumor Immune Evasion

ABSTRACT Immune checkpoint blockade (ICB) efficacy is limited by tumor‐intrinsic immune escape mechanisms. This study identifies the transcription factor ZBTB21 as a central orchestrator of dual immunosuppressive programs. ZBTB21 epigenetically silences gasdermin D (GSDMD)‐dependent pyroptosis by restricting STAT1‐mediated chromatin accessibility via H3K27ac modulation at the GSDMD locus. Simultaneously, it represses MHC‐I antigen presentation by attenuating IRF1 expression and its transactivation capacity. Genetic ablation of ZBTB21 unleashes pyroptotic cell death and enhances tumor antigen presentation, establishing a self‐reinforcing cycle that recruits and activates CD8 + T cells. This dual activation overcomes ICB resistance in murine models, while B2M deletion ablates efficacy, confirming MHC‐I dependency. Pharmacological inhibition of ZBTB21 with dobutamine disrupts its DNA‐binding domain, which triggers pyroptotic inflammation and MHC‐I upregulation to synergize with anti‐PD‐1 therapy. Thus, ZBTB21 represents a druggable nexus coordinating pyroptosis resistance and antigen presentation escape, providing a combinatorial strategy to reinvigorate antitumor immunity.