IFI30 promotes tumor-associated macrophage infiltration via activation of the ATF3-CCL5 axis in breast cancer

Public summary

* IFI30 drives immune-dependent breast cancer progression via epigenetic upregulation and the ATF3-CCL5 axis.

* IFI30 depletion reduces TAM infiltration and enhances CD8+ T cell accumulation, reshaping the tumor immune landscape.

* IFI30 is highly expressed in monocytes/macrophages, promoting M2-like polarization and PD-L1 expression.

* Targeting IFI30 disrupts both tumor-intrinsic and immune-regulatory pathways in breast cancer.

Abstract

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.