Targeting ERO1A enhances antitumor immune response by recruiting CD8+T cells and synergizing with PD-L1 blockade in liver cancer.

Despite the availability of various treatment modalities for liver cancer, its mortality rate remains high. Immunotherapy represents an emerging approach for liver cancer. However, the response rate to single-agent immune checkpoint blockade therapy is suboptimal. Endoplasmic reticulum oxidoreductase 1-alpha (ERO1A), a potential therapeutic target associated with endoplasmic reticulum (ER) stress, is implicated in impeding protective antitumor immunity. In this study, we found that targeting ERO1A in liver cancer, while activating the PERK/EIF2α/ATF4/CHOP-mediated apoptosis and autophagy signaling, downregulated ADORA1 and inhibited the cGMP/PKG pathway, thereby promoting the expression and secretion of CCL4. This led to an increased infiltration of CD8+T cells into the immune microenvironment, enhancing the antitumor immune response. Furthermore, targeting ERO1A in liver cancer also upregulated type I interferon synthesis, activated the JAK-STAT pathway, and promoted programmed cell death ligand 1 (PD-L1) and MHC-Ⅰ expression. Using liver cancer animal models, we demonstrated that combination treatment with ERO1A inhibitor and PD-L1 inhibitor increased CD8+T cell infiltration and enhanced their function within the tumor microenvironment, resulting in synergistic antitumor effects. Therefore, ERO1A represents a promising therapeutic target in liver cancer, potentially suitable for combination with immune checkpoint inhibitors to improve patient outcomes.