Related Experiment Video
Updated: Jun 25, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
YTHDF3 phase separation regulates HSPA13-dependent clear cell renal cell carcinoma development and immune evasion
Chenyun Dai1,2, Jianfu Cao1,2, Yuangui Tang1
1Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Abstract:
Insufficient understanding about the immune evasion mechanism leads to the inability in predicting current immunotherapy effects in clear cell renal cell carcinoma (ccRCC) and sensitizing ccRCC to immunotherapy. RNA binding proteins (RBPs) can promote tumor progression and immune evasion. However, research on RBPs, particularly m6A reader YTHDF3, in ccRCC development and immune evasion is limited. In this study, we found that YTHDF3 level was downregulated in ccRCC and was an independent prognostic biomarker for ccRCC. Decreased YTHDF3 expression was correlated with the malignancy, immune evasion, and poor response to anti-programmed death ligand 1 (PD-L1)/CTLA-4 in ccRCC. YTHDF3 overexpression restrained ccRCC cell malignancy, PD-L1 expression, CD8+ T cell infiltration and activities in vivo, indicating its inhibitory role in ccRCC development and immune evasion. Mechanistically, YTHDF3 WT was found to have phase separation characteristics and suppress ccRCC malignancy and immune evasion. Whereas YTHDF3 mutant, which disrupted phase separation, abolished its function. YTHDF3 enhanced the degradation of its target mRNA HSPA13 by phase separation and recruiting DDX6, resulting in the downregulation of the downstream immune checkpoint PD-L1. HSPA13 overexpression restored ccRCC malignancy and immune evasion suppressed by YTHDF3 overexpression. In all, our results identify a new model of YTHDF3 in regulating ccRCC progression and immune evasion through phase separation.
Insights
YTHDF3, a key RNA binding protein, is downregulated in clear cell renal cell carcinoma (ccRCC), hindering anti-cancer immunity. Restoring YTHDF3 levels suppresses tumor growth and enhances immunotherapy response in ccRCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) progression and immune evasion mechanisms remain poorly understood, limiting effective immunotherapy prediction and application.
- RNA binding proteins (RBPs) are implicated in tumor progression and immune evasion, but specific roles, like that of m6A reader YTHDF3, in ccRCC are underexplored.
Purpose of the Study:
- To investigate the role of YTHDF3 in ccRCC development, immune evasion, and response to immunotherapy.
- To elucidate the molecular mechanisms by which YTHDF3 regulates ccRCC progression and immune evasion.
Main Methods:
- Analysis of YTHDF3 expression levels in ccRCC tissues and correlation with clinical parameters, malignancy, and immune evasion.
- In vivo studies involving YTHDF3 overexpression in ccRCC models to assess its impact on tumor growth, PD-L1 expression, and T cell activity.
- Investigation of YTHDF3's phase separation characteristics and its interaction with DDX6 to regulate HSPA13 mRNA degradation and PD-L1 expression.
Main Results:
- YTHDF3 was found to be downregulated in ccRCC and served as an independent prognostic biomarker.
- Decreased YTHDF3 expression correlated with increased ccRCC malignancy, immune evasion, and poor response to PD-L1/CTLA-4 blockade.
- YTHDF3 overexpression inhibited ccRCC malignancy and immune evasion by promoting HSPA13 mRNA degradation via phase separation, leading to PD-L1 downregulation and enhanced CD8+ T cell activity.
Conclusions:
- YTHDF3 acts as a tumor suppressor in ccRCC, inhibiting progression and immune evasion.
- YTHDF3's function is dependent on its phase separation ability, which regulates HSPA13 mRNA degradation and subsequent PD-L1 expression.
- YTHDF3 represents a novel therapeutic target for enhancing immunotherapy efficacy in ccRCC.
