PAK4 inhibition enhances tumor immunity by inducing viral mimicry

Activating viral mimicry in cancer cells has emerged as a promising therapeutic strategy. Through a large-scale drug screen, we identified a PAK4 inhibitor as a negative regulator of SUV39H1, a histone methyltransferase critical for the transcriptional silencing of repetitive elements (REs) in cancer cells. Pharmacological inhibition or genetic depletion of PAK4 markedly reduced SUV39H1 expression, leading to RE de-repression, accumulation of cytoplasmic double-stranded RNA (dsRNA), and induction of DNA damage. These events activated interferon-stimulated genes (ISGs) through the MAVS and STING antiviral pathways, collectively recapitulating hallmarks of viral mimicry. Mechanistically, we found that PAK4 directly phosphorylates and stabilizes SUV39H1, whereas PAK4 depletion promotes CBL-mediated ubiquitination and proteasomal degradation of SUV39H1. Loss of PAK4 consequently reduced H3K9me3 occupancy at RE loci, thereby reactivating their transcription. In vivo, PAK4 knockdown or treatment with clinically available PAK4 inhibitor KPT-9274 significantly suppressed tumor growth and enhanced intratumoral infiltration of CD8⁺ T cells and natural killer (NK) cells. Clinically, PAK4 expression inversely correlated with LINE1-ORF1 levels in patient tumor samples, and lower PAK4 expression associated with improved patient survival. These findings identify PAK4 as a key regulator of SUV39H1 and REs, and promising therapeutic target in cancer.