SMC4 promotes immune evasion by inhibiting endogenous interferon signaling and upregulating PD-L1 expression in triple negative breast cancer

Objective: 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.

Method: 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.

Results: 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 CD8⁺T 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 CD8⁺T 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.

Conclusion: 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.

Immune evasion; PD-L1; SMC4; Triple negative breast cancer.