Immunotherapy has transformed cancer treatment,but its effectiveness in breast cancer remains suboptimal.Tumor-associated macrophages(TAMs),a key component of the tumor microenvironment(TME),contribute significantly t...Immunotherapy has transformed cancer treatment,but its effectiveness in breast cancer remains suboptimal.Tumor-associated macrophages(TAMs),a key component of the tumor microenvironment(TME),contribute significantly to immune evasion.In this study,we identified gamma-interferon-inducible lysosomal thiol reductase(IFI30)as a critical regulator of TAM function in breast cancer.IFI30 expression is upregulated in breast cancer via enhanced Histone 3 lysine 27 acetylation(H3K27ac)modification and promotes tumor progression and metastasis in an immune-dependent manner.Mechanistically,IFI30 in breast cancer cells recruits TAMs by activating the ATF3-CCL5 axis.Within macrophages,it promotes M2-like polarization and PD-L1 upregulation,fostering an immunosuppressive TME.Our findings established IFI30 as a promising therapeutic target for disrupting TAM-mediated immune suppression and enhancing breast cancer immunotherapy.展开更多
基金supported by the Beijing Natural Science Foundation(7252202 and 25JL008)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-029 and 2023-I2M-2-006,China)the National Natural Science Foundation of China(82304523).
文摘Immunotherapy has transformed cancer treatment,but its effectiveness in breast cancer remains suboptimal.Tumor-associated macrophages(TAMs),a key component of the tumor microenvironment(TME),contribute significantly to immune evasion.In this study,we identified gamma-interferon-inducible lysosomal thiol reductase(IFI30)as a critical regulator of TAM function in breast cancer.IFI30 expression is upregulated in breast cancer via enhanced Histone 3 lysine 27 acetylation(H3K27ac)modification and promotes tumor progression and metastasis in an immune-dependent manner.Mechanistically,IFI30 in breast cancer cells recruits TAMs by activating the ATF3-CCL5 axis.Within macrophages,it promotes M2-like polarization and PD-L1 upregulation,fostering an immunosuppressive TME.Our findings established IFI30 as a promising therapeutic target for disrupting TAM-mediated immune suppression and enhancing breast cancer immunotherapy.
