SOX30 Facilitates Triple-Negative Breast Cancer Metastasis via TNFR2-NF-κB Signaling and Tumor Microenvironment Remodeling.

Triple-negative breast cancer (TNBC) remains therapeutically challenging due to its aggressive metastatic potential, high recurrence rates, and lack of effective targeted therapies. Herein, we identified that SOX30 is significantly upregulated in TNBC and correlates with poor clinical prognosis. Functionally, SOX30 specifically drives TNBC metastasis and activates the TNFR2-mediated downstream NF-κB signaling cascade. Mass cytometry profiling of the tumor immune microenvironment revealed that SOX30 facilitates the recruitment of tumor-associated macrophages (TAMs) within pulmonary metastases, a finding corroborated by flow cytometric quantification. Mechanistically, downstream pathway analyses identified that SOX30 induces activation of the TNFR2-NF-κB axis and concurrently upregulates expression of the chemokine CCL20. Therapeutic intervention with CCL20 neutralizing antibodies or small-molecule CCR6 inhibitors effectively attenuated metastatic progression and abrogated TAM infiltration. Strikingly, combinatorial blockade using the TNFR2 inhibitor etanercept together with a CCR6 inhibitor exhibited superior anti-metastatic efficacy relative to control treatments. Collectively, our findings delineate a novel oncogenic SOX30-TNFR2-NF-κB-CCL20/CCR6 axis driving TNBC metastasis. These results establish SOX30 as a promising prognostic biomarker and a potential therapeutic target for anti-metastatic strategies in TNBC.