Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.

Breast cancer brain metastases (BCBM) are incurable, and new therapies are urgently needed. BCBM upregulates stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability. Here, we test the effect of a brain-penetrant, clinical-stage SCD inhibitor (SCDi) on breast cancer cells and mouse models of BCBM. We show that SCDi markedly reshapes the lipidome of breast cancer cells, resulting in endoplasmic reticulum stress, DNA damage, impaired DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolongs the survival of BCBM-bearing mice. Furthermore, pharmacological inhibition of SCD enhances antigen presentation by dendritic cells, increases interferon signaling, promotes the infiltration of cytotoxic T cells, and decreases the proportion of exhausted T cells and regulatory T cells (Tregs) in the tumor microenvironment (TME) in a syngeneic mouse model of BCBM. Additionally, SCDi reduces the engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes in the TME. These findings suggest that SCD inhibition could be an effective strategy to both intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM.