DNASE1L3 is a deoxyribonuclease that catalyzes internucleosomal DNA fragmentation during apoptosis and necrosis by cleaving both single- and double-stranded DNA to produce 3'-OH ends 1. Beyond apoptosis, DNASE1L3 plays critical roles in immune homeostasis: it degrades neutrophil extracellular traps (NETs) alongside DNASE1, preventing pathological clot formation and organ damage during inflammation 2. DNASE1L3 also suppresses anti-DNA autoimmunity by degrading DNA within apoptotic microparticles 1. Loss-of-function mutations cause systemic lupus erythematosus (SLE), characterized by rapid anti-dsDNA antibody responses through type I interferon-dependent extrafollicular B cell differentiation 3. DNASE1L3 deficiency is recognized as a monogenic form of lupus, highlighting its central role in self-antigen clearance 4. Beyond autoimmunity, emerging evidence demonstrates DNASE1L3's role in cancer immunotherapy: dendritic cell-expressed DNASE1L3 degrades tumor-associated NETs, promoting CD8+ T cell infiltration and enhancing anti-PD-(L)1 efficacy 5. Additionally, DNASE1L3 facilitates PANoptosis in hepatocellular carcinoma treated with tyrosine kinase inhibitors, augmenting anti-tumor immunity 6. Clinically, DNASE1L3 represents a promising biomarker for predicting immunotherapy response and disease outcomes 7.