Targeting E-Proteins Licenses cDC1 Immunogenicity for Potent Anti-Tumor Vaccination [RNA-seq]

Type 1 conventional dendritic cells (cDC1s) are essential for priming anti-tumor CD8⁺ T cells, yet the intrinsic pathways limiting their function remain unclear. Here we identify E-proteins (E2A/HEB) as a master checkpoint that actively suppresses cDC1 immunogenicity by directly transactivating PTEN, thereby restraining PI3K-AKT-mTOR signaling, FLT3L-driven proliferation, and NF-κB-mediated IL-12 production. Genetic ablation of E-proteins in DCs unleashes a hyperfunctional program—expanded cDC1 populations, enhanced antigen presentation, and superior CD8⁺ T cell priming—while deletion of the E-protein antagonist Id2 impairs cDC1 function, establishing a bidirectional rheostat. This axis is clinically relevant, as dynamic E-protein activity in human tumor DCs correlates with patient survival and response to immune checkpoint blockade. Finally, vaccination with E-protein-deficient DCs elicits potent antigen-specific T cell expansion and achieves robust therapeutic efficacy across multiple preclinical tumor models, defining a targetable checkpoint and establishing E-protein inactivation as a platform for next-generation cancer immunotherapies.