HDAC Inhibition Unlocks Tumor Plasticity and Enhances Immunotherapy Response in Myc-Driven Small Cell Lung Cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 15% of all lung cancer cases. Characterized by low immunogenicity, SCLC may utilize epigenetic mechanisms to evade immune detection. In this study, we demonstrate that entinostat, a class I histone deacetylase inhibitor, upregulates immune-related genes in human SCLC cells. In vivo, we confirmed that entinostat treatment increased the expression of immune checkpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model while shifting tumors from a neuroendocrine (NE)-high phenotype to a NE-low phenotype and was associated with increased T-cell infiltration. Notably, combining entinostat with anti–PD-1 immunotherapy suppresses tumor growth and significantly prolongs survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.