Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas

Sep 24, 2026

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Immune checkpoint inhibitor efficacy varies in clear-cell renal cell carcinoma (ccRCC), with primary resistance limiting durable benefit. The study integrates DNA methylation and transcriptome profiles to define a ccRCC subtype marked by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. An index of methylation-based epigenetic silencing (iMES) is developed and validated to predict resistance to ICI in the BIONIKK trial. High iMES links to VEGF pathway silencing, endothelial depletion, immune activation/suppression dynamics, EZH2 activation, BAP1/SETD2 loss, and potential benefit from combination therapies.

LanguageEnglish

CategoryHealthcare

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Pages24

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Graphical abstract and highlights

Molecular index iMES and prediction of ICI outcomes

Mechanistic links to EZH2, BAP1/SETD2 and VEGF/angiogenesis

Summary

Introduction

Article Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas Graphical abstract Highlights d Gene silencing inﬂuences both ccRCC aggressiveness and microenvironment d A methylation index (iMES) reliably predicts ICI treatment outcomes in ccRCC d Elevated iMES correlates with EZH2 activation and BAP1/ SETD2 deﬁciency d iMES and angiogenesis jointly impact response to immunotherapy in ccRCC Authors Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, ..., Catherine Sautes-Fridman, St´ephane Oudard, Gabriel G. Malouf Correspondence [maloufg@igbmc.fr](maloufg@igbmc.fr) In brief Lu et al. develop an index of methylationbased epigenetic silencing (iMES) signature and unveils its potential to predict immunotherapy outcomes in clear-cell renal cell carcinoma (ccRCC), unlocking the intricate relationship between the tumor microenvironment and promoter methylation. Intriguingly, endothelial cell depletion corresponds to VEGF pathway methylation, proposing a link between iMES, angiogenesis, and immunotherapy response in ccRCC patients. Lu et al., 2023, Cell Reports Medicine 4, 101287 November 21, 2023 ª 2023 The Authors. [https://doi.org/10.1016/j.xcrm.2023.101287](https://doi.org/10.1016/j.xcrm.2023.101287) ll ll OPEN ACCESS Article Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas Xiaofan Lu,1,16 Yann-Alexandre Vano,2,3,16 Xiaoping Su,4,16 Alexandra Helleux,1 V´eronique Lindner,5 Roger Mouawad,6 Jean-Philippe Spano,6 Morgan Roupr^et,7 Eva Comp´erat,8 Virginie Verkarre,9 Cheng-Ming Sun,3 Mostefa Bennamoun,10 Herv´e Lang,11 Philippe Barthelemy,12 Wenxuan Cheng,13 Li Xu,13 Irwin Davidson,1 Fangrong Yan,13 Wolf Herv´e Fridman,3 Catherine Sautes-Fridman,3 St´ephane Oudard,3,15,17 and Gabriel G. Malouf1,14,15,17,18,* 1Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France 2Department of Medical Oncology, H^opital Europ´een Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Universit´e Paris Cit´e , Paris, France 3Centre de Recherche Cordeliers, INSERM 1138, Universit´e de Paris Cit´e, Sorbonne Universit´e, Equipe labellis´ee Ligue contre le Cancer, 75006 Paris, France 4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5Department of Pathology, Strasbourg University Hospital, Strasbourg, France 6Department of Medical Oncology, Sorbonne University, AP-HP, H^opital Piti´e-Salp^etri`ere, Paris, France 7Sorbonne University, GRC 5 P, UKredictive Onco-Uro, AP-HP, Urology, Piti´e-Salp^etri`ere Hospital, 75013 Paris, France 8Department of Pathology, Sorbonne University, AP-HP, H^opital Tenon, Paris, France 9Department of Pathology, H^opital Europ´een Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Universit´e Paris Cit´e, Paris, France 10Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France 11Department of Urology, Strasbourg University Hospital, Strasbourg, France 12Department of Medical Oncology, Strasbourg University, Institut de Canc´erologie de Strasbourg, Strasbourg, France 13Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P. R. China 14Department of Medical Oncology, Strasbourg University, Institut de Canc´erologie de Strasbourg, Strasbourg, France 15Senior author 16These authors contributed equally 17These authors contributed equally 18Lead contact *[Correspondence:](Correspondence: maloufg@igbmc.fr)[ maloufg@igbmc.fr](Correspondence: maloufg@igbmc.fr)[ ](Correspondence: maloufg@igbmc.fr)[https://doi.org/10.1016/j.xcrm.2023.101287](https://doi.org/10.1016/j.xcrm.2023.101287) SUMMARY The efﬁcacy of immune checkpoint inhibi

FAQs

What does the iMES signature predict in clear-cell renal cell carcinoma?

iMES predicts primary resistance to immune checkpoint inhibition in ccRCC, based on methylation-based epigenetic silencing features.

How is iMES linked to the tumor microenvironment?

High iMES is associated with VEGF pathway silencing, endothelial cell depletion, and immune activation/suppression patterns that collectively shape immunotherapy response.

What biological factors are associated with elevated iMES?

Elevated iMES correlates with EZH2 activation and BAP1/SETD2 deficiency, supporting an epigenetic mechanism underlying immunotherapy resistance.

Sep 24, 2026

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