Intron retention regulates STAT2 function and associates with immunotherapy response in lung cancer

Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and enabled considerable therapeutic advances for treating various diseases, including lung cancer. However, the molecular determinants of variable patient outcomes remain unclear. Using long-read RNA sequencing, we mapped the landscape of alternative RNA splicing in human primary lung adenocarcinomas. We identified more than 149,000 full-length messenger RNA (mRNA) isoforms, more than half of which were unannotated and many that occurred in immune-related genes, particularly within the type I interferon response pathway. We functionally characterized retained introns in the STAT2 gene that produced altered protein isoforms that regulated immune signaling and interferon responses and correlated with patient survival after anti–programmed death-ligand 1 (PD-L1) immunotherapy. These findings position alternative splicing as a regulator of tumor immune responses and reveal intron retention in STAT2 as an interferon regulatory axis that correlates with PD-L1 checkpoint inhibitor response.