Advertisement

ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI188801

Tumoral RCOR2 promotes tumor development through dual epigenetic regulation of tumor plasticity and immunogenicity

Lei Bao,1 Ming Zhu,1 Maowu Luo,1 Ashwani Kumar,2 Yan Peng,1 Chao Xing,2 Yingfei Wang,1 and Weibo Luo1

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Bao, L. in: PubMed | Google Scholar |

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Zhu, M. in: PubMed | Google Scholar |

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Luo, M. in: PubMed | Google Scholar

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Kumar, A. in: PubMed | Google Scholar

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Peng, Y. in: PubMed | Google Scholar

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Xing, C. in: PubMed | Google Scholar |

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Wang, Y. in: PubMed | Google Scholar |

1Department of Pathology, UT Southwestern Medical Center, Dallas, United States of America

2Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Luo, W. in: PubMed | Google Scholar |

Published July 3, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188801.
Copyright © 2025, Bao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 3, 2025 - Version history
View PDF
Abstract

Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+/CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+/CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti-PD-1 therapy in mouse models of cancer and correlated with better response to anti-PD-1 therapy in human patients. Collectively, these findings uncover a “two birds with one stone” effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (July 3, 2025): In-Press Preview
Advertisement
Advertisement