FABP4/5-Mediated Lipid Reprogramming Is Associated with Immunosuppressive T Cell Crosstalk in Cervical Cancer After Chemoradiotherapy.

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer, but resistance and recurrence remain major clinical challenges. Tumor immune-metabolic reprogramming profoundly affects treatment response and immune evasion; however, the molecular mechanisms of lipid metabolism remodeling and its interaction with T cells after CCRT in cervical cancer are still unclear. This study aimed to investigate how CCRT-induced metabolic changes in cervical cancer cells influence T cell function and immune evasion. Methods: We performed metabolic pathway activity analysis, cell-cell communication prediction, and transcriptomic analysis on paired single-cell transcriptomic data from three cervical cancer patients before and after CCRT (n = 3 paired). Validation was conducted using multiple independent GEO cohorts, in vitro cell culture experiments, and multi-sample immunofluorescence staining. Results: CCRT was associated with upregulation of FABP4/5 in malignant epithelial cells and activation of the PPAR and adipocytokine signaling pathways, leading to lipid metabolic reprogramming. Epithelial cells with high FABP4/5 expression showed enhanced predicted intercellular communication with T cells via the computationally inferred ligand-receptor axes PTGER4 and CXCR4. T cells with high communication intensity exhibited an immunosuppressive phenotype signature, accompanied by metabolic alterations in lipid and carbohydrate pathways and enrichment of regulatory T cell subsets. Validation experiments confirmed the association between FABP4/5 and inhibitory T cells. Conclusions: This study suggests that FABP4/5-mediated lipid metabolism reprogramming may represent a key mechanism contributing to the immunosuppressive crosstalk between cervical cancer epithelial cells and T cells after CCRT. Targeting this axis may reverse T cell dysfunction and provide a potential immunometabolic strategy to reduce post-CCRT recurrence.