Abstract C094: Tumor-associated fibroblasts drive taurine accumulation and radiotherapy resistance in renal cell caecinoma via the CXCL12/CXCR4/SLC6A6 axis

Abstract Background Renal cell carcinoma (RCC) is a highly heterogeneous malignancy with limited sensitivity to conventional radiotherapy. Although radiotherapy is increasingly employed in the management of oligometastatic and unresectable RCC, resistance to ionizing radiation remains a major clinical obstacle. The molecular mechanisms underlying radioresistance in RCC are not fully elucidated. Tumor-associated fibroblasts (CAFs), as key components of the tumor microenvironment, have been implicated in therapeutic resistance across multiple cancer types. However, their specific contribution to radiotherapy resistance in RCC remains poorly defined. Methods Primary CAFs and normal fibroblasts (NFs) were isolated from human RCC tissues. Single-cell RNA sequencing of treatment-naïve tumors was performed to analyze stromal composition and CXCL12 expression. RCC cells were stimulated with recombinant CXCL12 and subjected to transcriptomic, proteomic, and metabolomic profiling to evaluate alterations in taurine metabolism and transporter expression. In vitro co-culture systems and clonogenic survival assays were utilized to assess radiosensitivity, while ferroptosis was evaluated by measuring lipid peroxidation. In vivo, RCC cells were co-injected with CAFs into immunodeficient mice, followed by radiotherapy with or without the CXCR4 inhibitor AMD3100. Results Clinicopathological analysis revealed that RCC patients with high CAF infiltration exhibited reduced radiotherapy responsiveness. Single-cell RNA sequencing showed increased CAF abundance and elevated CXCL12 expression in resistant cases. In vitro, co-culture with CAFs induced radioresistance in RCC cells. Metabolomic profiling revealed that CXCL12 stimulation elevated intracellular taurine levels, while transcriptomic and proteomic data indicated upregulation of the taurine transporter SLC6A6. Functional assays demonstrated that SLC6A6-mediated taurine accumulation suppressed ferroptosis and conferred radioresistance. Inhibition of CXCR4 with AMD3100 abrogated taurine accumulation, restored ferroptosis sensitivity, and enhanced radiotherapy efficacy both in vitro and in vivo. Conclusions This study uncovers a previously unrecognized mechanism by which CAFs confer radiotherapy resistance in RCC via CXCL12/CXCR4-driven metabolic reprogramming. The CXCL12/CXCR4/SLC6A6 axis represents a potential therapeutic target to overcome RCC radioresistance and highlights the pivotal role of CAF-derived metabolic cues in modulating tumor response to radiation. Citation Format: Qiwen Pan, liru He. Tumor-associated fibroblasts drive taurine accumulation and radiotherapy resistance in renal cell caecinoma via the CXCL12/CXCR4/SLC6A6 axis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C094.