Abstract 6152: The inhibition of USP18 enhanced cancer immunogenicity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer, which exhibits highly metastasis and shows poorly response to many treatments. Immune checkpoint blockage (ICB) treatment induces anti-tumor effect by innate immune activation for tumor clearance. Nevertheless, ICB was shown to be effective in “hot” tumor microenvironment representing highly immune infiltration. Turning “cold” tumor into “hot” tumor may enhance ICB treatment in TNBC. Type I interferon (IFN) response regulates inflammation and immune modulation. However, IFN-response is abated by USP18, suggesting that inhibiting USP18 could enhance IFN signaling and tumor immunogenicity. To study USP18 inhibition, we employed CRISPR-Cas9 to engineered mutated-USP18 in TNBC cell lines. Mass spectrometry-based proteomic study of mutated-USP18 revealed the induction of IFN-response, cytokine response, MHC-I antigen presentation, while reduced cell proliferation- and cell motility- related pathways under IFN-modulation in TNBC cells. These proteome alterations further caused enhanced-cytotoxic effect of NK cells by inducing apoptotic-mediated cancer cell death in co-culture system. In vivo tumors with mutated USP18 also showed increased immune activation, suggesting that this loss of USP18 functions could enhance the immune response within the tumor microenvironment. This may lead to the enhancement of ICB treatment for TNBC. Our finding demonstrated that the inhibition of USP18 potentially enhanced IFN-response mediating hot tumor microenvironment by promoting cancer immunogenicity in TNBC. This inhibition of USP18 approach may hold promise for boosting the effectiveness of ICB therapies in TNBC. Citation Format: Chartinun Chutoe, Valerie G. Brunton, Alexander Von Kriegsheim. The inhibition of USP18 enhanced cancer immunogenicity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6152.