Sammarco Alessandro, Guerra Giorgia, Eyme Katharina M, Kennewick Kelly, Qiao Yu, El Hokayem Joelle, Williams Kevin J, Su Baolong, Cakici Cagri, Mnatsakanyan Hayk, Zappulli Valentina, Bensinger Steven J, Badr Christian E
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Commun Biol. 2025 Apr 4;8(1):562. doi: 10.1038/s42003-025-07977-1.
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.
乳腺癌脑转移（BCBM）无法治愈，因此迫切需要新的治疗方法。BCBM会上调硬脂酰辅酶A去饱和酶（SCD），这是一种催化单不饱和脂肪酸合成的酶，提示其可能存在代谢脆弱性。在此，我们测试了一种可穿透血脑屏障的临床阶段SCD抑制剂（SCDi）对乳腺癌细胞和BCBM小鼠模型的作用。我们发现，SCDi显著重塑了乳腺癌细胞的脂质组，导致内质网应激、DNA损伤、DNA损伤修复受损及细胞毒性。重要的是，单独使用SCDi或与聚（ADP-核糖）聚合酶（PARP）抑制剂联合使用可延长荷BCBM小鼠的生存期。此外，在同基因BCBM小鼠模型中，对SCD的药理学抑制增强了树突状细胞的抗原呈递，增加了干扰素信号传导，促进了细胞毒性T细胞的浸润，并降低了肿瘤微环境（TME）中耗竭T细胞和调节性T细胞（Tregs）的比例。此外，SCDi减少了免疫抑制途径的参与，包括TME中的程序性死亡受体1（PD-1）：程序性死亡受体配体1/程序性死亡受体配体2（PD-L1/PD-L2）和脊髓灰质炎病毒受体（PVR）/T细胞免疫球蛋白和ITIM结构域（TIGIT）轴。这些发现表明，抑制SCD可能是一种有效的策略，既能从本质上减少肿瘤生长，又能重新编程脑微环境中的抗肿瘤免疫以治疗BCBM。
