Abstract Brain metastasis in breast cancer represents a devastating, end-stage event, with median survival measured in months. This underscores the urgent need for novel therapeutic strategies. Breast cancers that metastasize to the brain face a nutrient-poor and immune suppressive environment and considered an immue excluded or ‘cold’ tumor. These tumors exhibit metabolic reprogramming, relying heavily on acetate as a carbon source. The enzyme acetyl-CoA synthetase 2 (ACSS2) converts acetate into acetyl-CoA and has emerged as a critical regulator of this adaptation. Here, we show that breast cancer brain metastatic (BCBM) cells express significantly higher ACSS2 levels compared to their parental counterparts and that ACSS2 is required for BCBM growth in vivo. Mechanistically, ACSS2 promotes BCBM survival by suppressing ferroptosis, a form of immunogenic cell death (ICD), through E2F1-mediated regulation of the cystine-glutamate transporter SLC7A11. Treatment with our newly developed brain-penetrant ACSS2 inhibitor (ACSS2i) in a syngeneic BCBM model significantly reduced tumor growth in vivo. Consistent with inducing ICD, single-cell RNA sequencing analysis revealed increased infiltration of NK and T cells in ACSS2i–treated tumors, with elevated expression of CD8, CD4, and CD28. Furthermore, conditioned media from ACSS2 inhibitor-treated BCBM cells enhanced dendritic cell (DC) maturation in vitro, as indicated by upregulation of costimulatory molecules CD86 and CD40. Lastly, flow cytometry data shows that BCBM tumors treated with ACSS2 inhibitors increased immune infiltration of adaptive T and B cells, number of monocytes and DCs. Thus, targeting ACSS2 triggers ferroptotsis, reduced BCBM growth and reshapes the brain tumor microenvironment to enhance immune cell infiltration and potentially convert a ‘cold’ tumor into an immune-inflamed ‘hot’ tumor. Citation Format: Riley G. Young. Targeting ACSS2 promotes ferroptosis and immune cell infiltration in breast cancer brain metastases abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr B066.
Riley Young (Mon,) studied this question.