METRN modulates immune escape via CD8(+) T cells in breast cancer progression through IL-6 signaling pathway.

BACKGROUND: Breast cancer remains one of the most prevalent and lethal cancers among women, with a notable risk of recurrence and metastasis. Meteorin (METRN) is a newly discovered cytokine that plays a critical role in neurodevelopment and immune regulation. However, its involvement in breast cancer, particularly in modulating the immune microenvironment, is not well understood. This study aims to investigate the role of METRN in breast cancer progression and to elucidate its potential function in regulating interleukin-6 (IL-6)-mediated cluster of differentiation 8 positive (CD8(+)) T cell activity. METHODS: We used bioinformatics tools to analyze METRN's diagnostic and prognostic value in breast cancer, validated the findings with clinical samples, and examined METRN's effects on cell behavior using MCF-7, MDA-MB-231, and SKBR3 cell lines. We assessed cell proliferation, migration, invasion, and apoptosis, and studied METRN's interaction with IL-6 in modulating CD8(+) T cell function using enzyme-linked immunosorbent assay (ELISA) and quantitative PCR (qPCR). In vivo, tumor growth was evaluated in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, which lack adaptive immunity and thus reflect tumor cell-intrinsic effects. RESULTS: Bioinformatics analysis showed that METRN was highly expressed in breast cancer and correlated with poor prognosis. METRN inhibition reduced tumor cell proliferation, migration and invasion, while increasing apoptosis. In vitro co-culture assays showed that METRN knockdown increased IL-6 production and enhanced CD8(+) T-cell effector function, whereas IL-6 silencing abrogated these effects. CD8 staining was also performed and was shown for completeness. However, given that NOD/SCID mice lacked adaptive immunity, these signals cannot be interpreted as functional CD8(+) T-cell infiltration, but were presented as technical staining results. CONCLUSIONS: METRN promotes breast cancer progression through tumor-intrinsic mechanisms, while in vitro and bioinformatics analyses further indicate that METRN regulates IL-6-linked CD8(+) T-cell activity. These findings highlight METRN as a potential biomarker and therapeutic target in breast cancer, while further validation in immunocompetent or humanized mouse models will be required to assess its role in immunotherapy.