2. Academic Validation
  3. HDAC inhibition unlocks tumor plasticity and enhances immunotherapy response in Myc-Driven Small Cell Lung Cancer

HDAC inhibition unlocks tumor plasticity and enhances immunotherapy response in Myc-Driven Small Cell Lung Cancer

  • bioRxiv. 2025 Aug 9:2025.08.06.668958. doi: 10.1101/2025.08.06.668958.
Azam Ghafoor 1,  Linying Zhu 2 3,  Zoe Weaver Ohler 4,  Rajaa El Meskini 4,  Devon Atkinson 4,  Amanda Day 4,  Laura Bassel 4,  Weixin Wang 5,  Haoxuan Ying 2 3,  Katherine R Calvo 5,  Lorinc Pongor 1 6,  Yves Pommier 7,  Anish Thomas 7,  Yilun Sun 2 3
Affiliations

Affiliations

  • 1 Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • 2 University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.
  • 3 Department of Pharmacology and Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
  • 4 Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD.
  • 5 Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
  • 6 HCEMM Cancer Genomics and Epigenetics Core Group, Szeged, Hungary.
  • 7 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
PMID: 40970137 DOI: 10.1101/2025.08.06.668958
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. Here, we demonstrate that entinostat, a class I histone deacetylase inhibitor (HDACi) upregulates immune-related genes in human SCLC cells. In vivo, we confirmed entinostat treatment increased expression of immunecheckpoint 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 to a NE-low phenotype. Notably, combining entinostat with anti-PD-1 immunotherapy significantly enhances T-cell infiltration, suppresses tumor growth, and prolongs survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the immunological landscape and NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.

Keywords

anti-PD-1 therapy; entinostat; histone deacetylase inhibitor (HDACi); immunotherapy; neuroendocrine; small cell lung cancer (SCLC).

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