RNASET2 is a secreted ribonuclease with dual roles in innate immunity and cancer suppression. As a ribonuclease, it cleaves single-stranded RNA preferentially between purine and uridine residues, generating degradation products including purine-2',3'-cyclophosphate-terminated oligoribonucleotides and 2',3'-cyclic guanosine monophosphate 12. These products activate toll-like receptors TLR8 and TLR7, triggering innate immune responses 12. RNASET2 also degrades mitochondrial RNA and processes cytosolic non-coding RNAs imported into mitochondria 34. Beyond its enzymatic function, RNASET2 acts as an oncosuppressor, suppressing tumor growth and metastasis in ovarian cancer through mechanisms independent of ribonuclease catalytic activity 5. It functions as an alarmin-like molecule, promoting M1-polarized macrophage recruitment and activation while suppressing pro-tumoral M2 polarization 67. However, RNASET2 demonstrates context-dependent roles: elevated plasma RNASET2 levels associate with increased lung adenocarcinoma and prostate cancer risk 89, while upregulation in renal cell carcinoma predicts poor prognosis 10. These findings suggest RNASET2 has pleiotropic, cell-type and cancer-type-specific effects warranting careful therapeutic consideration.