CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer

Sep 21, 2026

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Background Circular RNAs (circRNAs) are implicated in gastric cancer progression, but the link between dysregulated circRNAs, immune escape, and immunotherapy efficacy remains unclear. This study investigates how circRNA dysregulation influences gastric cancer immunotherapy and identifies molecular therapeutic targets. Methods CircRNA sequencing profiled differential circRNA expression across paired tumor and adjacent tissues; circRHBDD1 was validated by qRT-PCR and functional assays. Survival analyses and loss- and gain-of-function studies assessed immune escape, while sequencing, immunoprecipitation, flow cytometry, and meRIP clarified mechanisms. Results circRHBDD1 upregulation correlated with poor survival, increased PD-L1, and reduced CD8+ T-cell infiltration; it modulated IGF2BP2 ubiquitination and PD-L1 stability via m6A. Nanoparticles delivered circRHBDD1 siRNA combined with anti-PD-1 showed safe, effective immunotherapy effects. Conclusion circRHBDD1 promotes immune escape and T-cell immune reprogramming by elevating PD-L1, suggesting inhibition as a strategy to improve treatment outcomes and enabling a feasible nanodrug delivery approach.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusion

Introduction

Epidemiology and current treatment challenges

Need for combined immunotherapy

Li et al. Journal of Translational Medicine (2024) 22:704 [https://doi.org/10.1186/s12967-024-05498-9](https://doi.org/10.1186/s12967-024-05498-9) Journal of Translational Medicine RESEARCH Open Access CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts asa nanotherapeutic target in gastric cancer Yanna Li 1†, Zhixiong Wang 1†, Peng Gao 1†, Danping Cao 1†, Runyu Dong 1, Menglin Zhu 1, Yao Fei 1, Xueliang Zuo 1,2* and Juan Cai2,3* Abstract Background Circular RNAs (circRNAs) have been implicated in the development and progression of gastric cancer (GC). However, it remains unclear whether dysregulated circRNA affects immune escape and the efficacy of immunotherapy in GC. Our aim is to investigate the molecular mechanism of circRNA affecting GC immunotherapy and identify effective molecular therapeutic targets. Methods The differential expression profile of circRNAs was established through circRNA sequencing, comparing three paired GC tissues with their adjacent non-cancerous gastric tissues. The expression level of circRHBDD1 in GC tissues was then assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) . The biological characteristics of circRHBDD1 were verified through a series of experiments, including agarose gel electrophoresis assays, RNase R treatment, and actinomycin D experiments. The prognostic value of circRHBDD1 in GC was evaluated by conducting both univariate and multivariate survival analyses. Furthermore, loss-and gain-of-function approaches were utilized to investigate the impact of circRHBDD1 on GC immune escape. RNA-sequencing, immunoprecipitation, flow cytometry, and methylated RNA immunoprecipitation (meRIP) analysis were performed to elucidate the underlying molecular mechanisms. Results We discovered that circRHBDD1 exhibited remarkably high expression level s in GC tissues and cell lines. Notably, the high expression of circRHBDD1 was significantly correlated with poor overall survival and disease free survival among GC patients. Both in vitro and in vivo experiments revealed that circRHBDD1 upregulated the expression of PD-L1 and impeded the infiltration of CD8+ T cells. Further, we found that circRHBDD1 binds to IGF2BP2, disrupting the interaction between E3 ligaseTRIM25 and IGF2BP2, and ultimately inhibiting IGF2BP2 ubiquitination and degradation. Intriguingly, IGF2BP2 enhances PD-L1 mRNA stability through m6A modification. Additionally, we developed Poly (lactide-co-glycol ic acid) (PLGA)-Polyethylene glycol (PEG)-based nanoparticles loaded with †Yanna Li, Zhixiong Wang, Peng Gao and Danping Cao contributed equally to this work. *Correspondence: Xueliang Zuo[zuoxueliang0202@126.com](zuoxueliang0202@126.com)[ ](zuoxueliang0202@126.com)Juan Cai [caijuan1987@yeah.net](caijuan1987@yeah.net) 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/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.0/)) applies to the data made

FAQs

What is the study aimed at determining about circRHBDD1 in gastric cancer?

The study investigates the molecular mechanism by which circRHBDD1 affects gastric cancer immune escape and immunotherapy efficacy, with the goal of identifying actionable molecular therapeutic targets.

How does circRHBDD1 influence immune escape according to the results?

circRHBDD1 increases PD-L1 expression and impedes CD8+ T-cell infiltration in vitro and in vivo, leading to poorer clinical outcomes.

What molecular pathway links circRHBDD1 to PD-L1 regulation?

circRHBDD1 binds IGF2BP2, disrupting TRIM25–IGF2BP2 interaction to inhibit IGF2BP2 ubiquitination and degradation; IGF2BP2 then enhances PD-L1 mRNA stability via m6A modification.

How was circRHBDD1 targeted for immunotherapy and what did the combination show?

PLGA-PEG nanoparticles loaded with circRHBDD1 siRNA were tested, and in vivo experiments showed that combining PLGA-PEG(si-circRHBDD1) with anti-PD-1 was safe and effective for cancer immunotherapy.

Sep 21, 2026

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