Circular RNA circTNK2 contributes to immune evasion and acts as a nanotherapeutic target in tamoxifen-resistant ER-positive breast cancer

circTNK2, a circular RNA, is significantly overexpressed in tamoxifen-resistant breast cancer tissues and is linked to poor prognosis. circTNK2 encodes a novel 487-amino acid protein, termed C-TNK2-487aa, which inhibits the recruitment of natural killer (NK) cells. Mechanistic studies reveal that C-TNK2-487aa interacts with STAT3 and promotes its phosphorylation in ER-positive breast cancer cells. The increased phosphorylated STAT3 then competes with STAT1 binding, inhibiting the formation of STAT1 homodimers required for CXCL10 transcription, ultimately leading to immune evasion. Additionally, circTNK2 binds to SRSF1 and promotes tamoxifen resistance and breast cancer cell proliferation. Co-delivery of circTNK2 antisense oligonucleotides (ASO) and CXCL10 plasmid DNA mediated by BC-targeting ZIF-8 nanoparticles markedly suppresses breast cancer growth, reverses tamoxifen resistance, and increases tumor infiltration of CD56+ NK cells in vivo. These findings underscore the critical role of the circTNK2-encoded peptide in tamoxifen resistance and immune evasion, providing a therapeutic vulnerability in treating tamoxifen-resistant breast cancer. Overall design: To investigate the roles of circRNAs in ER-positive, tamoxifen-resistant breast cancer, we collected three tamoxifen-sensitive and three tamoxifen-resistant ER-positive breast cancer tumor samples.We conducted circRNA expression profiling using circRNA-seq data from these samples.Comparative analysis of circRNA expression profiles revealed differentially expressed circRNAs between the two groups. To elucidate how C-TNK2-487aa contributes to the progression of ER-positive breast cancer, we established MCF7-Pa cells (MCF7 parental, tamoxifen sensitive cell line) that overexpress either circTNK2IRES-Mut or circTNK2. We then performed gene expression profiling using RNA-seq data from these modified cells, with two biological replicates for each group. Comparative analysis of gene expression profiles identified differentially expressed genes (DEGs) between the two groups.