TFRC-mediated immune exclusion as a therapeutic vulnerability in cervical cancer: A comprehensive analysis based on...

Advanced and recurrent cervical cancer (CC) remains a clinical challenge due to limited therapeutic options and a poor 5-year survival rate (<20%). While immunotherapy has reshaped the treatment landscape, primary resistance driven by immune exclusion often limits its efficacy. This study aims to identify the key molecular determinants governing T-cell infiltration and to develop a robust prognostic framework by systematically analyzing the cancer immunoediting process.

We integrated transcriptomic data from TCGA and multiple GEO cohorts (n = 7) with CIC scores via the Tumor Immunotherapy Gene Expression Resource (TIP). Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify gene modules negatively correlated with T-cell infiltration (Step 5 of CIC). A refined prognostic signature was constructed using an ensemble of machine learning algorithms, including LASSO, Random Forest, and XGBoost. The clinical relevance, immune microenvironment landscape, and single-cell expression patterns of the lead candidate, TFRC, were validated using multi-omics integration. Finally, the oncogenic role of TFRC was characterized through in vitro functional assays and an in vivo xenograft model.

WGCNA identified a key module of 973 genes significantly associated with impaired T-cell recruitment. A 4-gene prognostic model (FOXRED2, RAB5IF, SHC1, TFRC) was developed, demonstrating high predictive accuracy for 1-, 3-, and 5-year overall survival (AUC up to 0.74), which was further validated in independent cohorts. Among these, TFRC emerged as a critical biomarker, showing significant overexpression in CC tissues and correlating with disease progression. Bioinformatic analysis linked high TFRC expression to a "cold" tumor microenvironment characterized by reduced CD8+ T-cell infiltration and elevated TIDE exclusion scores. Functionally, TFRC silencing significantly suppressed CC cell proliferation, migration, and invasion, and markedly attenuated tumor growth in nude mice.

Our study provides a novel CIC-based stratification tool for CC patients and identifies TFRC as a pivotal regulator of immune exclusion. These findings suggest that targeting TFRC not only inhibits intrinsic tumor progression but also potentially sensitizes CC to immunotherapy by remodeling the immune microenvironment.