Abstract 2798: CD112 drives tumor immune evasion in HER2-positive breast cancer through sphingolipid metabolism-dependent remodeling of CD8+T cell receptor landscapeand consequent dysfunction

Abstract Purpose: HER2-positive breast cancer (HER2+BC) features high TMB and abundant TILs, supporting immunotherapy potential. HER2-targeted therapies also engage the immune system. However, PD-1/PD-L1 inhibitors show limited efficacy, suggesting unique immunosuppressive mechanisms in this subtype. Methods: Integrated analysis of FUSCC and validation cohorts identified key immune checkpoints. Experimental validation was performed through knockdown of candidate immune checkpoints and in vivo screening. Mouse scRNA-seq revealed CD8+ T cells as the most impaired subset. CD112-high tumor cells were characterized via stable cell lines and multi-omics analysis, with validation by spatial transcriptomics. TurboID proximity labeling identified CD112-UGCG interaction. CD8+ T cell function was assessed using conditioned medium co-culture and exogenous GlcCer supplementation. To demonstrate that CD112-driven sphingolipid metabolism exerts its function through CD112-CD112R axis, we utilized Cd112r-KO mice. Results: We revealed that non-pCR HER2-positive patients have a comparable level of TILs but exhibited a more exhausted phenotype, and found significant upregulation of CD112 in residual tumors following HER2-targeted therapy. Moreover, while PD-L1 is highly expressed in TNBC, CD112 shows specific enrichment in HER2+BC, with predominant localization to malignant epithelial cells. These findings suggest that CD112 may hold greater therapeutic potential in HER2+BC. In addition to its canonical immunosuppressive function, our study revealed that CD112 promotes the metabolism of sphingolipid, particularly glycosphingolipid. Mechanistically, through TurboID we uncovered a previously unreported interaction between CD112 and the key enzyme UGCG in Golgi, which prevents UGCG degradation and thereby elevates glycosphingolipid level. Functional experiments demonstrated that CD112-mediated suppression of CD8+T cells is partially dependent on its regulation of sphingolipid metabolism. By altering the glycosphingolipid content of exosomal membranes, CD112-high tumor cells leads to the aberrant aggregation of CD112 key receptor-CD112R in lipid rafts of neighboring CD8+T cells, which increases CD112-CD112R interaction frequency and amplifies suppression effect. For furture in vivo translation, a combination therapy of anti-HER2, anti-CD112R, and a UGCG inhibitor is proposed. Conclusion: We identified CD112 as a key immunosuppressive regulator in HER2+BC, surpassing PD-L1. We also revealed a metabolism-dependent mechanism of CD112-mediated immunosuppression executed through the CD112-UGCG-GlcCer axis. Inhibition of this axis may further enhances the efficacy of anti-CD112R treatment in HER2+BC, presenting a promising combination strategy. Citation Format: YI ZHANG, Bingqiu Xiu, Jiong Wu, Qi Zhang, . CD112 drives tumor immune evasion in HER2-positive breast cancer through sphingolipid metabolism-dependent remodeling of CD8+T cell receptor landscapeand consequent dysfunction abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2798.