SLC7A11 as a Prognostic Biomarker and Therapeutic Target in Renal Cell Carcinoma: Insights into Tumor Microenvironment Remodeling and Immune Infiltration
Xinyang Cheng, Jun Zhang, Jixin Yuan, Jingze Xu, Wenjuan Gan, Zhifei Cao, Yongsheng ZhangIntroduction:
SLC7A11 is part of the solute carrier family and encodes the transporter xCT. However, its functional role in renal cell carcinoma (RCC) progression and associated tumor microenvironment (TME) modulation remains poorly characterized and requires further investigation. This study aimed to explore SLC7A11 expression patterns and their prognostic value, focusing on changes in TME and immune cell infiltration dynamics.
Methods:
Multi-omics data from TCGA, GTEx, and four GEO cohorts were analyzed, followed by immunohistochemical validation on 498 clinical renal specimens. Bioinformatic tools, including co-expression networks, GSEA, ESTIMATE, CIBERSORT, TIMER2.0, and Kaplan-Meier survival analysis, were applied to dissect signaling pathways and immune infiltration. SiRNA-mediated SLC7A11 knockdown in 786-O and OSRC2 cell lines was conducted to detect cell proliferation, migration, invasion, and cell cycle changes.
Results:
SLC7A11 was significantly upregulated in KIRC, KIRP and KICH compared with normal renal tissues (P<0.05). SLC7A11-related genes were enriched in cell cycle, DNA replication, p53, ferroptosis, and IL-17 pathways. High SLC7A11 correlated with elevated tumor-associated macrophages and reduced CD8+ T cells, predicting poor overall survival. Knocking down SLC7A11 suppressed malignant phenotypes of RCC cells, induced G0/G1 arrest, and downregulated Cyclin D1/Cyclin B1.
Discussion:
SLC7A11 exerted oncogenic effects across all primary RCC subtypes. SLC7A11 remodeled the TME by recruiting and polarizing tumor-associated macrophages. Mechanistically, it promoted RCC progression by activating cell cycle pathways to sustain unrestrained cell proliferation. The crosstalk among SLC7A11, ferroptosis, and immune signaling provides new evidence for combining ferroptosis induction with immunotherapy in RCC treatment.
Conclusion:
SLC7A11 was an adverse prognostic biomarker overexpressed in all main RCC subtypes. It remodeled the TME by weakening the immune response via macrophages and disrupting normal cell growth regulation. Targeting SLC7A11 was a promising combinatorial therapeutic strategy for RCC.