Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma

Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA Sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase-stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.