RNASE1 encodes a secreted ribonuclease that catalyzes RNA cleavage on the 3' side of pyrimidine nucleotides, functioning on both single-stranded and double-stranded RNA [UniProt]. Beyond its classical extracellular RNA degradation role, RNASE1 exhibits dual intracellular and extracellular functions with significant disease relevance. Intracellularly, RNASE1 localizes predominantly to the nucleus where it inhibits gene expression and suppresses colorectal cancer cell proliferation, with high expression associated with better patient survival 1. The protein also impairs CD8+ T-cell function by entering T cells and deactivating STAT1, leading to reduced effector cytokine expression and increased immune checkpoint protein levels 2. In cancer contexts, RNASE1 promotes immunosuppression by inducing macrophage M2 polarization through ALK signaling activation, contributing to therapy resistance in hepatocellular carcinoma and non-small cell lung cancer 34. However, RNASE1 also shows protective functions, as extracellular RNA degradation by RNase1 can reduce cardiac ischemia/reperfusion injury by disrupting TNF-α/TNF-R1-mediated inflammatory pathways 5. Clinically, RNASE1 expression serves as a biomarker for treatment response and disease progression across multiple cancer types, with therapeutic targeting of RNase1-ALK interactions showing promise for cancer immunotherapy.