Sun Mouyuan, Zhang Quanjie, He Zhixu, Luo Yaxian, Tu Yan, Peng Lianjie, Mao Huchao, Zhang Jingyu, Qiu Tao, Zhang Yan
Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Stomatology Hospital, School of Stomatology, Zhejiang Universit School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
ACS Omega. 2025 Jun 4;10(23):24655-24674. doi: 10.1021/acsomega.5c01496. eCollection 2025 Jun 17.
Recently, immunogenic cell death (ICD) has been identified as a regulatory cell death mechanism that induces an adaptive immune response, thereby improving enhancing the efficacy of immunotherapy and contributing to improved prognosis in bladder cancer (BLCA). This study established a risk signature based on ICD and identified ICD-related genes as diagnostic markers and therapeutic targets for BLCA. Thirty-two key ICD-risk genes (IRGs) were screened from correlation and univariate Cox regression analyses. Data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases regarding BLCA and normal samples were categorized based on IRGs. ICD-based prognostic signature was built based on IRGs, stratifying BLCA patients into high- and low-risk groups. SLC2A3 was identified as a hub gene by 101 combinatorial machine learning algorithms and 10 individual machine learning algorithms. Based on single-cell sequencing data, we identified the cancer-associated fibroblasts (CAFs), the key cell population exhibiting high SLC2A3 expression. Functional analyses were performed to explore the potential value of SLC2A3 as a target for precision therapy. A prognostic signature was constructed using IRGs, indicating significant differences in the tumor microenvironment (TME) and treatment response between different risk groups. We identified SLC2A3 as the most critical IRG exhibiting high expression in the fibroblast population of patients with BLCA, especially in CAFs, which play an important role in BLCA progression. We found that inhibiting SLC2A3 expression may enhance the effectiveness of immunotherapy and the identified potential drugs targeting SLC2A3. We demonstrated that the identified IRGs serve as risk factors for clinical prognosis in BLCA and successfully constructed an ICD-based prognostic signature. Additionally, SLC2A3 holds potential as a therapeutic target to advance precision and personalized treatment strategies for BLCA, in combination with immunotherapy.
最近，免疫原性细胞死亡（ICD）已被确定为一种调节性细胞死亡机制，可诱导适应性免疫反应，从而提高免疫治疗的疗效并有助于改善膀胱癌（BLCA）的预后。本研究基于ICD建立了一个风险特征，并将ICD相关基因鉴定为BLCA的诊断标志物和治疗靶点。通过相关性和单变量Cox回归分析筛选出32个关键的ICD风险基因（IRGs）。从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）获得的关于BLCA和正常样本的数据根据IRGs进行分类。基于IRGs构建了基于ICD的预后特征，将BLCA患者分为高风险和低风险组。通过101种组合机器学习算法和10种个体机器学习算法将SLC2A3鉴定为枢纽基因。基于单细胞测序数据，我们鉴定出癌症相关成纤维细胞（CAFs），这是表现出高SLC2A3表达的关键细胞群体。进行功能分析以探索SLC2A3作为精准治疗靶点的潜在价值。使用IRGs构建了一个预后特征，表明不同风险组之间在肿瘤微环境（TME）和治疗反应方面存在显著差异。我们将SLC2A3鉴定为在BLCA患者的成纤维细胞群体中高表达的最关键IRG，尤其是在CAFs中，其在BLCA进展中起重要作用。我们发现抑制SLC2A3表达可能会增强免疫治疗的效果，并鉴定出靶向SLC2A3的潜在药物。我们证明所鉴定的IRGs是BLCA临床预后的风险因素，并成功构建了基于ICD的预后特征。此外，SLC2A3作为推进BLCA精准和个性化治疗策略的治疗靶点具有潜力，可与免疫治疗相结合。
