Integrated Multiomics Analysis and Machine Learning Approaches in Bladder Cancer: Unveiling the Impact of Immunogenic Cell Death and Its Key Gene SLC2A3 on Prognosis and Personalized Treatment Strategies.

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.