DNASE1L3-mediated PANoptosis enhances the efficacy of combination therapy for advanced hepatocellular carcinoma.

The introduction of combination therapy utilizing tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) has significantly altered the management of affected patients. However, the absence of predictive biomarkers to identify those who would derive the greatest benefit from this combination therapy underscores the necessity for further enhancements in its efficacy. In this study, we performed a proteomic analysis on surgical specimens from patients who either responded to or did not respond to combination therapy with sorafenib and programmed death-1 (PD-1) monoclonal antibody (mAb). We employed experiments, including immunocytochemistry, co-immunoprecipitation, and transmission electron microscopy, to elucidate the mechanism of DNASE1L3-induced PANoptosis. Additionally, we assessed the function of DNASE1L3 in combination therapy using a mouse liver orthotopic tumor model and clinical samples. Our findings indicated that the levels of deoxyribonuclease 1 like 3 (DNASE1L3) were significantly elevated in the cohort of patients who responded to treatment, correlating with the sorafenib-induced programmed cell death (PCD) of HCC cells. Further experimentation revealed that DNASE1L3 facilitated the generation of double-strand deoxyribonucleic acid (dsDNA) breaks and activated the absent in melanoma 2 (AIM2) pathway during sorafenib-induced HCC cell death, ultimately culminating in PANoptosis. Moreover, DNASE1L3-induced PANoptosis augmented the activation of anti-tumor immunity within the tumor microenvironment (TME), thereby enhancing the efficacy of the combination therapy involving sorafenib and PD-1 mAb. Our findings offer valuable insights into the mechanisms underlying DNASE1L3's role in sorafenib sensitivity and position DNASE1L3 as a promising predictive biomarker and target for improving outcomes in combination therapy for HCC.