Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma

Sep 21, 2026

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Metastatic clear cell renal cell carcinoma patients often fail to benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic combination therapy, creating an urgent need for predictive biomarkers. This study investigates the roles of pleckstrin homology-like domain family A members in ccRCC, using integrated transcriptomic, clinical, genetic, and DNA methylation analyses from TCGA plus local RNA-seq. Results link elevated PHLDA2 to worse prognosis, DNA hypomethylation-driven upregulation, and an immunosuppressive microenvironment, confirmed in three RCT validations.

LanguageEnglish

CategoryResearch & Report

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Pages19

Reading Time48 min

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Abstract

Background

Methods

Results

Conclusions

Introduction

Clinical context and treatment landscape

Zhao et al. European Journal European Journal of Medical Research (2024) 29:378 [https://doi.org/10.1186/s40001-024-01939-9](https://doi.org/10.1186/s40001-024-01939-9 of Medical Research)[ of Medical Research](https://doi.org/10.1186/s40001-024-01939-9 of Medical Research) RESEARCH Open Access Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma Junjie Zhao1†, Xiuyi Pan2†, Zilin Wang1†, Yuntian Chen3, Dingbang Liu 1, Yu Shen 1, Xinyuan Wei1, Chenhao Xu1, Xingming Zhang1, Xu Hu1, Junru Chen1, Jinge Zhao1, Bo Tang1, Guangxi Sun1, Pengfei Shen1, Zhenhua Liu 1*†, Hao Zeng1*† and Jiayu Liang1*† Abstract Background A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown. Methods Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation. Results Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2 . An immunosuppressive microenvironment featured by high infiltrates ofTregsand cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed. | † Junjie Zhao, Xiuyi Pan and Zilin Wang contributed equally. | | --- | | †Zhenhua Liu, Hao Zeng and Jiayu Liang jointly supervised this work. | *Correspondence: Zhenhua Liu [Zhenhuazhliu@scu.edu.cn](Zhenhuazhliu@scu.edu.cn)[ ](Zhenhuazhliu@scu.edu.cn)Hao Zeng [kucaizeng@163.com](kucaizeng@163.com)[ ](kucaizeng@163.com)Jiayu Liang [jiayu.liang@scu.edu.cn](jiayu.liang@scu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[http://creativeco](http://creativeco)[mmons.org/publicdomain/zero/1.0/](mmons.org/publicdomain/zero/1.0/)) applies to the data

FAQs

Why is PHLDA2 investigated in clear cell renal cell carcinoma?

PHLDA family members are implicated in multiple cancers, while their specific roles in ccRCC were unknown. The study aims to identify whether PHLDA2 relates to tumor biology and therapy outcomes in ccRCC.

What data sources and analyses were used?

Integrated transcriptomic, clinical, genetic alteration, and DNA methylation data were analyzed from TCGA. RNA sequencing was performed on primary tumors and normal kidney tissues from the authors’ center, complemented by functional pathway analyses and validation using three randomized controlled trials.

How does PHLDA2 relate to prognosis and immune microenvironment?

Higher PHLDA2 expression is associated with adverse clinicopathologic parameters and poorer prognosis in ccRCC. It is also linked to aberrant DNA hypomethylation and an immunosuppressive microenvironment characterized by increased Tregs and cancer-associated fibroblasts.

Sep 21, 2026

Uploaded by Maeve