SNORD50A/B disassemble ASC-1 complex to silence NF-kB and boost PD-1 blockade in non-small-cell lung cancer

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) have increasingly been linked to tumorigenesis due to their high frequency of deletion across multiple cancer types. However, their biological roles in non-small-cell lung cancer (NSCLC) remains to be systematically investigated. In this study, we observed that SNORD50A/B were frequently deleted in lung adenocarcinomas and this molecular event was strongly linked to poor patient survival. Subsequent in vitro and in vivo studies demonstrated the tumor-suppressive role of SNORD50A/B in NSCLC. Mechanistically, SNORD50A/B directly bound to activating signal cointegrator 1 complex subunit 1 (ASCC1), preventing its interaction with activating signal cointegrator 1 (ASC-1) and disrupting the integrity of ASC-1 complex, which attenuates NF-kB transcriptional activity and down-regulates PD-L1 expression. Synthetic Snord50a/b-loaded cationic liposomes showed the potent anti-tumor effects and sensitized NSCLC cells to anti-PD-1 immunotherapy. Taken together, SNORD50A/B exert tumor-suppressive effects by disrupting ASC-1 complex to silence NF-kB, highlighting its therapeutic potential via cationic liposomes for treating SNORD50A/B-deficient tumors.