Ren Tingrong, Wei Gaigai, Yi Jingjing, Zhang Yuqi, Zhao Haiping, Wu Nana, Zhang Huiling, Guo Zhihan, Wang Yihan, Kuang Jiating, Sheng Zhaoying, Zhang Duanwu
Children's Hospital of Fudan University, National Children's Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, Fudan University, Shanghai, China.
Front Immunol. 2025 Aug 11;16:1612461. doi: 10.3389/fimmu.2025.1612461. eCollection 2025.
Aberrant pre-mRNA splicing is increasingly recognized as a key contributor to tumorigenesis and immune evasion. However, the regulatory factors orchestrating splicing dynamics within the tumor microenvironment (TME) remain incompletely understood. Here, we identify GPATCH3, a previously uncharacterized G-patch domain-containing protein, as a critical modulator of alternative splicing and immune regulation in cancer.
We employed biochemical studies, splicing reporter assays, and transcriptomic analyses to elucidate the function of GPATCH3. and models, including GPATCH3-depleted cell lines and mouse xenografts, were used to assess its roles in tumor progression. Immune infiltration patterns were analyzed using TIMER2.0 based on TCGA transcriptomic data.
GPATCH3 interacts with the RNA helicase DHX15 and enhances its ATPase activity, promoting proper spliceosome disassembly. Loss of GPATCH3 led to splicing alterations, including in immunoregulatory genes such as , , and . Functional studies revealed that GPATCH3 deficiency attenuated tumor growth . Conversely, elevated GPATCH3 expression was associated with reduced infiltration of cytotoxic T cells and NK cells, alongside an enrichment of immunosuppressive populations such as MDSCs and CAFs across multiple cancer types. Transcriptomic analysis further revealed that GPATCH3 deficiency upregulates immunomodulatory genes such as and , suggesting a role in shaping the TME via splicing regulation.
Our findings suggest GPATCH3 as a critical regulator that governs alternative splicing and immunosuppressive microenvironment remodeling. By modulating the splicing fidelity of key immune genes and altering their expression, GPATCH3 may facilitate immune escape and tumor progression. These results provide mechanistic insights into how RNA splicing factors interface with immune regulation and highlight GPATCH3 as a potential therapeutic target for immunomodulatory cancer therapy.
异常的前体mRNA剪接越来越被认为是肿瘤发生和免疫逃逸的关键因素。然而，在肿瘤微环境（TME）中协调剪接动态的调控因子仍未完全明确。在此，我们鉴定出GPATCH3，一种先前未被描述的含G-结构域的蛋白质，它是癌症中可变剪接和免疫调节的关键调节因子。
我们采用生化研究、剪接报告基因检测和转录组分析来阐明GPATCH3的功能。使用包括GPATCH3缺失的细胞系和小鼠异种移植模型来评估其在肿瘤进展中的作用。基于TCGA转录组数据，使用TIMER2.0分析免疫浸润模式。
GPATCH3与RNA解旋酶DHX15相互作用并增强其ATP酶活性，促进剪接体的正确解体。GPATCH3的缺失导致剪接改变，包括免疫调节基因如 、 和 中的改变。功能研究表明，GPATCH3的缺乏减弱了肿瘤生长 。相反，GPATCH3表达升高与细胞毒性T细胞和NK细胞浸润减少相关，同时在多种癌症类型中富集了免疫抑制群体，如MDSC和CAF。转录组分析进一步表明，GPATCH3的缺乏上调了免疫调节基因如 和 ，表明其通过剪接调节在塑造TME中发挥作用。
我们的研究结果表明GPATCH3是控制可变剪接和免疫抑制微环境重塑的关键调节因子。通过调节关键免疫基因的剪接保真度并改变其表达，GPATCH3可能促进免疫逃逸和肿瘤进展。这些结果为RNA剪接因子如何与免疫调节相互作用提供了机制见解，并突出了GPATCH3作为免疫调节癌症治疗的潜在治疗靶点。
