ELF3 crotonylation-mediated crosstalk with ubiquitination suppresses immune escape in cervical cancer through the induction of DNA replication stress

DNA replication stress is a prevalent feature in carcinogenesis. Irreparable DNA damage leads to genomic instability and the accumulation of cytosolic DNA, thereby activating the innate immune response and contributing critically to tumor suppression. However, the role of DNA replication stress remains poorly characterized in cervical cancer. By means of single-cell RNA sequencing analysis, we identified ELF3 as a key transcription factor mediating DNA replication stress in cervical cancer. ELF3 is upregulated in cervical cancer. Mechanistically, upon DNA damage, ELF3 protein abundance is reduced due to p300-mediated crotonylation at lysine residues K318 and K320, which enhances its ubiquitination and subsequent proteasomal degradation, thereby compromising ELF3 protein stability. Depletion of ELF3 suppresses RFC3 transcription and impedes cell cycle progression. Furthermore, either mimicking ELF3 crotonylation or knocking down ELF3 results in the accumulation of cytosolic DNA, triggering the cGAS-STING signaling pathway and activating innate immunity. Consequently, tumor cells recruit and activate CD8 + T cells via the macrophage migration inhibitory factor (MIF)–CD74/CXCR4 receptor–ligand axis, leading to suppressed tumor growth and enhanced responsiveness to anti–PD-1 immunotherapy. In conclusion, our findings demonstrate that targeting ELF3 represents a promising therapeutic strategy to potentiate immunotherapy in cervical cancer, offering novel mechanistic insights and a theoretical foundation for improving clinical outcomes.