YTHDC2 manipulates anti-tumoral macrophage polarization and predicts favorable outcomes in triple negative breast cancer.

Triple-negative breast cancer (TNBC) possesses high malignant and metastatic rates among all subtypes. Chemotherapy is a standard of care for TNBC but only a small moiety of patients achieved complete relief (CR) after chemotherapy. The recent concept of tumor ecosystem has provided new insights into solutions from an approach of enhancing anti-tumoral immunity of macrophages. We hereby observed a positive correlation of YTHDC2 abundance with anti-tumoral gene markers of macrophages. YTHDC2-high macrophages also exerted interactions with other immune cells such as T helper cells, cytotoxic T cells, and NK cells. Further investigation on the transcriptional regulatory network identified six transcriptional factors upregulated by YTHDC2, and they together influenced the expressions of TWISTNB and the oncogene MYC. Additionally, our survival analysis prompted that YTHDC2 is prognostic of higher chemo-therapeutic efficacy and better survival outcomes. We demonstrated that ample macrophage YTHDC2 indicates anti-tumoral phenotype polarization and propitious survival outcome in post-treatment TNBC patients (Clinical trial registry name: Chinese Clinical Trial Registry, Registration No.: ChiCTR2400084513, Registration Date: 2024-05-20).