RNA-Binding Protein CSTF2 Drives Immune Evasion and Malignant Progression in Breast Cancer by Degrading THSD1 mRNA

Resistance to immunotherapy in breast cancer (BC) is intimately connected to the dynamic tumor immunoediting process. RNA-binding proteins (RBPs) are recognized as pivotal modulators of BC advancement. Cleavage stimulation factor 2 (CSTF2), a core factor involved in mRNA 3'-end maturation, shows significant overexpression in numerous cancers and is correlated with adverse clinical outcomes. However, the precise molecular mechanisms through which it drives malignancy by regulating immunoediting remain incompletely understood.

This study performed a systematic evaluation of CSTF2's expression profile and prognostic significance in BC using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). CSTF2 expression was modulated via knockdown and overexpression approaches to study core malignant traits, such as proliferative capacity and cell migration. The role of CSTF2 in immunoediting was examined through immune landscape analysis and flow cytometry.

Integrated bioinformatics identified a regulatory pathway whereby CSTF2 induces transcriptional upregulation of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) by promoting degradation of thrombospondin type-1 domain-containing protein 1 (THSD1) mRNA. The consequent increase in PD-L1 expression potently inhibits CD8⁺ T cell-mediated tumoricidal activity, thereby facilitating immune escape and collectively accelerating malignant progression in BC.

This study delineates the detailed molecular mechanisms by which the RBP CSTF2 exacerbates malignant progression, offering fresh theoretical insights and potential targets for targeted immunotherapeutic strategies in BC.