Zhu Jiayu, Zhang Lei, Hui Xue, Shang Lingmin, Ma Jianli, Zhang Qingyuan
Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
Int Immunopharmacol. 2025 Dec 3;166:115580. doi: 10.1016/j.intimp.2025.115580. Epub 2025 Sep 20.
Triple-negative breast cancer (TNBC) is highly invasive and has an inferior prognosis, with the majority of patients deriving limited benefits from immunotherapy. Enhancing the efficacy of immune checkpoint inhibitors (ICIs) remains a formidable challenge for TNBC. Structural maintenance of chromosome 4 (SMC4), a regulator of genomic stability, has been implicated in tumor progression. However, its role in TNBC immune evasion remains unknown.
SMC4 expression and spatial distribution in TNBC were analyzed using bioinformatics, immunohistochemistry, rt-qPCR and western blot. Immunohistochemistry was used to evaluated the association of SMC4 expression with immunotherapy response in advanced TNBC. Stable SMC4-knockdown and overexpression TNBC cell lines were established to assess tumor biology in vitro and in vivo, particularly its regulation of CD8 T cell function in the tumor microenvironment (TME). Flow cytometry was used to characterize CD8 T cell phenotypes. Western blot, RT-qPCR, ELISA, molecular docking and immunoprecipitation were used to evaluate the mechanism of SMC4 regulation of immune escape.
We demonstrated that SMC4 is aberrantly overexpressed in TNBC and correlates with diminished immunotherapeutic response and unfavorable prognosis. Intriguingly, SMC4 drives tumor progression in a CD8T cell-dependent manner, unveiling its non-canonical role in immune modulation. Mechanistically, SMC4 executes dual immunosuppressive functions hand, SMC4 maintains genomic stability to suppress cGAS-STING-mediated type I interferon production and CD8 T cells recruitment. In contrast, SMC4 directly impaired CD8T cell cytotoxicity through STING-independent PD-L1 upregulation. Knockdown SMC4 not only restored tumor immunogenicity, but also potentiated the efficacy of anti-PD-1 therapy in immunocompetent 4T1 murine models.
Our findings establish SMC4 as a dual regulator of immune evasion in TNBC and propose targeting SMC4 as a promising combinatorial strategy to overcome the current limitations in immunotherapy.
三阴性乳腺癌（TNBC）具有高度侵袭性，预后较差，大多数患者从免疫治疗中获得的益处有限。提高免疫检查点抑制剂（ICIs）的疗效仍然是TNBC面临的巨大挑战。染色体结构维持蛋白4（SMC4）是一种基因组稳定性调节剂，与肿瘤进展有关。然而，其在TNBC免疫逃逸中的作用尚不清楚。
利用生物信息学、免疫组织化学、rt-qPCR和蛋白质印迹法分析TNBC中SMC4的表达和空间分布。采用免疫组织化学评估SMC4表达与晚期TNBC免疫治疗反应的相关性。建立稳定的SMC4敲低和过表达TNBC细胞系，以评估体外和体内的肿瘤生物学特性，特别是其对肿瘤微环境（TME）中CD8 T细胞功能的调节。采用流式细胞术鉴定CD8 T细胞表型。利用蛋白质印迹法、RT-qPCR、酶联免疫吸附测定、分子对接和免疫沉淀法评估SMC4调节免疫逃逸的机制。
我们证明SMC4在TNBC中异常高表达，与免疫治疗反应降低和不良预后相关。有趣的是，SMC4以CD8 T细胞依赖的方式驱动肿瘤进展，揭示了其在免疫调节中的非经典作用。从机制上讲，SMC4具有双重免疫抑制功能。一方面，SMC4维持基因组稳定性以抑制cGAS-STING介导的I型干扰素产生和CD8 T细胞募集。另一方面，SMC4通过不依赖STING的PD-L1上调直接损害CD8 T细胞的细胞毒性。敲低SMC4不仅恢复了肿瘤免疫原性，还增强了抗PD-1疗法在具有免疫活性的4T1小鼠模型中的疗效。
我们的研究结果确定SMC4是TNBC免疫逃逸的双重调节因子，并提出靶向SMC4作为一种有前景的联合策略，以克服当前免疫治疗的局限性。
