According to the World Health Organization, breast cancer accounted for an estimated 2.1 million new cases and 627,000 deaths in 2018. Despite numerous efforts to enhance outcomes, breast cancer remains the most lethal cancers for women worldwide [1], [2]. Though immunotherapy targeting the PD-1/PD-L1 checkpoint has demonstrated remarkable efficacy in various cancers, breast cancer exhibits a notably low response rate to these interventions [3], [4]. These outcomes not only question the long-term benefit of PD-1 inhibitors but also cast doubt on the biomarker value of PD-L1 expression which had formed the basis for Food and Drug Administration (FDA) approval [5]. The suboptimal response in breast cancer may be attributed to factors such as a relatively low mutational burden in tumors, a tumor microenvironment that suppresses the immune system through regulatory T cells and macrophages, and limited access to the tumor microenvironment for T-effector cells [6], [7]. Blocking PD-1/PD-L1 signaling has shown significant improvement in T cell responses and clinical outcomes in various advanced malignancies [8]. Therefore, uncovering the mechanism of PD-L1 regulation and developing additional predictive and therapeutic markers for PD-1/PD-L1-based therapies in breast cancer are necessary [9], [10].

The gene IFI30 encodes the protein GILT, also known as gamma-interferon-inducible lysosomal-thiol reductase, predominantly found in antigen-presenting cells (APCs). Although there is low expression in T cells and fibroblasts, GILT plays a crucial role in antigen presentation [11], [12], [13], [14], [15]. Protein structure analysis showed GILT has 261 amino acids, including 224 amino acid precursor and 37 functional signal sequences. After translation from ribosomes, it is targeted to endosomes via mannose-6-phosphate (M6P) to the related receptor. In the endosomes, GILT undergoes cleavage of N-terminal and C-terminal pro-peptides to form the mature protein, which can exert its functions through endosomes, lysosomes, or direct secretion [16].

It has been reported that IFI30 plays a crucial role in the presentation of antigens for MHC II molecules by reducing disulfide bonds and unfolding epitopes [16], [17]. What sets IFI30 apart from other antigen-processing enzymes is its optimal activity at the acidic pH of lysosomes, where disulfide bonds are challenging to catalyze by other reductases [18], [19]. In this context, IFI30 represents the sole acidic enzyme involved in antigen hydrolysis and presentation, particularly for complex protein structures stabilized by disulfide bonds.

Elevated expression of IFI30 in T cells has been associated with compromised proliferation ability and cytotoxic effects [12]. Conversely, T cells deficient in IFI30 protein exhibited increased cell cycles and elevated CD69 expression, a membrane indicator of T cell activation. This unique characteristic was further supported by exacerbated diabetes symptoms induced by streptozotocin and reduced autoimmune vitiligo in IFI30-knockout mice [20], [21]. Moreover, IFI30 was implicated in promoting negative selection of thymocytes, including TRP1. GILT-deficient mice showed an increased proportion of TRP1-specific CD4+ single-positive thymocytes in peripheral blood [22]. GILT was discovered to enhance MHC class I-mediated antigen presentation and improve specific CD8 + T cell anti-tumor responses in murine colon carcinoma. These findings suggest that boosting the GILT-MHC-I axis in tumors could be a viable option for enhancing the immune system’s response against cancer [23]. The pathological analysis of breast tumors reveals that IFI30 exhibits high expression in breast tumor cells and is correlated with low positivity of CD8 cells in the tissue.

IFI30 overexpression in breast cancer has been associated with significant improvements in disease-free survival, inhibition of cancer cell growth and invasion, and enhanced sensitivity to standard treatments. Furthermore, GILT exhibited the ability to suppress reactive oxygen species (ROS) and autophagy, contributing to its overall impact on tumor growth [24]. Additionally, the circular RNA CircIFI30 was identified as a potential competing endogenous RNA (ceRNA) for miR-520b-3p, thereby negating the suppressive effect on the target gene CD44[25].

Herein, we provided a comprehensive review of the literature on IFI30 expression in breast cancer cells and its impact on immunotherapy outcomes Flow cytometry analysis revealed an increase in the population of CD86-positive macrophages related with IFI30 overexpression. The expression level of IFI30 was either increased or decreased in the breast cancer cell lines MDA-MB-231 and MDA-MB-453, affecting the gene and protein expression of PD-L1, with both showing consistent trends. Through functional analysis of database information, we identified a correlation between IFI30 expression in breast cancer and the efficacy of PD-L1 drugs. Our findings suggest that breast cancer immune intervention and immune checkpoint blockade (ICB) response in this cancer entity are influenced by IFI30, positioning it as a central factor and a promising predictor and driver in our study.