This study first reveals the critical role of glutamine metabolism-related transporter SLC25A22 in the cervical squamous cell carcinoma (CSCC) immune microenvironment. Through integrated metabolomic and transcriptomic analysis, it identifies SLC25A22 as a core regulator in glutamine metabolism, immune checkpoint activation, and impaired CD8+ T-cell cytotoxicity. Using 3D tumor organoids and animal models, the authors demonstrate that targeting SLC25A22 effectively restores CD8+ T-cell function and enhances anti-PD-1 therapy sensitivity, offering a novel therapeutic strategy for CSCC patients.
Literature Overview
This article, "Targeting Glutamine Metabolism Transporter SLC25A22 Enhances CD8+ T-Cell Function and Anti-PD-1 Therapy Efficacy in Cervical Squamous Cell Carcinoma," published in Advanced Science, reviews the metabolic and immune microenvironment characteristics of cervical squamous cell carcinoma (CSCC) and explores the therapeutic potential of targeting glutamine metabolism transporter SLC25A22.
Background Knowledge
CSCC is a common malignant tumor in women with limited current treatment efficacy, particularly low response rates to PD-1 immunotherapy. Recent advances highlight tumor microenvironment (TME) and metabolic reprogramming as key factors in tumor immune escape and therapeutic resistance. Glutamine metabolism serves as a crucial energy source for cancer cell proliferation and survival while affecting T-cell function. Based on multi-omics analysis of 44 CSCC and 18 normal tissue samples, this study first establishes the association between enhanced glutamine metabolism and immune checkpoint activation, identifying SLC25A22 as a potential therapeutic target. Using 3D organoid models and animal experiments, the authors confirm that targeting SLC25A22 enhances CD8+ T-cell cytotoxicity and improves PD-1 therapy effectiveness, particularly for PD-L1-high patients. This work provides theoretical foundations for future clinical trials combining metabolic regulation with immunotherapy.
Research Methods and Experiments
This study conducted integrated metabolomic and transcriptomic analysis to compare metabolic and gene expression profiles between 44 CSCC patients and 18 normal tissue samples. Clinical validation was performed using immunohistochemistry (IHC), multiplex IHC (mIHC), and flow cytometry. A 3D CSCC organoid model was developed and co-cultured with CD8+ T cells to simulate tumor-immune interactions within the TME. Finally, therapeutic efficacy of SLC25A22 targeting combined with anti-PD-1 treatment was evaluated in mouse xenograft models.
Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically elucidates the molecular mechanisms linking glutamine metabolism dysregulation and immune escape in CSCC, establishing SLC25A22 as a novel therapeutic target. Future clinical trials should evaluate V-9302's safety and efficacy in CSCC patients while investigating response variations across different PD-L1 expression levels. Additionally, organoid-based high-throughput screening platforms can accelerate discovery of other metabolic regulators, supporting personalized immunotherapy strategies.
Conclusion
This research comprehensively demonstrates the correlation between glutamine metabolism dysregulation and immune escape in CSCC, identifying SLC25A22 as a critical regulatory factor. Using 3D organoid and animal models, the authors confirm that targeting this transporter significantly enhances CD8+ T-cell function and improves anti-PD-1 therapy efficacy, particularly in PD-L1-high patients. These findings provide theoretical foundations for developing combined metabolic-immunotherapy strategies and establish a basis for future clinical trials. The study expands understanding of CSCC's metabolic microenvironment while offering actionable targets to improve immunotherapy responses, holding significant translational potential.
