Targeting Glutamine Metabolism Transporter SLC25A22 Enhances CD8+ T‐Cell Function and Anti‐PD‐1 Therapy Efficacy in Cervical Squamous Cell Carcinoma: Integrated Metabolomics, Transcriptomics and T‐Cell‐Incorporated Tumor Organoid Studies

Abstract Cervical squamous cell carcinoma(CSCC) represents formidable challenge in clinical oncology, exacerbated by poor prognosis and resistance to current treatments, including anti‐PD‐1 therapy, highlighting the urgent need for alternative therapeuties. Metabolic characteristics have emerged as potential drivers of treatment resistance and immune evasion. Herein, 1) based on metabolomic and transcriptomic analyses of 44 CSCC and 18 normal tissues, glutamine‐enriched and immunosuppressive microenvironment is identified in CSCC. 2) Integrative metabolomic and transcriptomic analyses revealed the glutamine metabolism transporter SLC25A22 as a key mediator in high glutamine metabolism, immune checkpoint activation and CD8+T‐cell cytotoxicity. 3) Immunohistochemistry(IHC), multiplex IHC, and flow cytometry validation with clinical CSCC samples revealed not only increased SLC25A22, PD‐1 expression and reduced CD8+T‐cell cytotoxicity in CSCC but also increased SLC25A22 expression in high PD‐L1 expressed CSCC patients, suggesting the potential of targeting SLC25A22 for enhancing CD8+T‐cell cytotoxicity and improving anti‐PD‐1 efficacy, especially in high PD‐L1 expressed patients. 4) Novelly, 3D‐CSCC organoids are constructed, replicating parental tumor features, and 3D‐T‐cell‐incorporated CSCC organoid models, replicating the interaction between tumor cells and CD8+T cells, for in vitro experiments. 5) Importantly, it is validated through in vitro 3D T‐cell‐incorporated CSCC organoid models and in vivo animal experiments that targeting the glutamine metabolism transporter SLC25A22, showed promise in enhancing CD8+T‐cell cytotoxicity and sensitizing anti‐PD‐1 therapy. These findings provided insights for future clinical trials exploring metabolic modulation to improve immunotherapy responses in CSCC patients.