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

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.