Abstract Immune checkpoint blockade (ICB) therapies have reshaped the treatment paradigm across various cancer types. In hepatocellular carcinoma (HCC), the combination of anti-PD-L1 and anti-VEGF, approved as new first-line treatment, has shown improved overall survival. However, response rate remains modest, driving the development of immunotherapy-based combination strategies. Our in-house clinical single cell RNAseq data revealed that transforming growth factor-beta (TGF-β) expression was widespread across multiple cell types in the tumor microenvironment (TME) and up-regulated in non-responders. Furthermore, TREM2+ macrophages were identified as the top predicted receiver, and their abundance was also increased in non-responders. Based on these findings, we administered Vactosertib, a TGF-β receptor (TGFBR1) inhibitor, combined with anti-PD-1, in our HCC resistant mouse model. This combination effectively overcame ICB resistance and significantly reduced TREM2+ macrophages. These findings confirm the important role of TGF-β in driving ICB resistance, potentially through TREM2+ macrophages that promote an immunosuppressive TME. Future studies will focus on uncovering how TGF-β modulates TREM2+ macrophages to support immune evasion and therapeutic resistance. Targeting this axis may offer an effective strategy to overcome resistance and improve the clinical efficacy of immunotherapy in HCC. Our long-term goal is to understand how TGF-β influences the phenotype and function of macrophages, leading to a new design of novel combination treatments that can enhance anti-tumor immunity and improve responses to immune checkpoint blockade. Citation Format: Yan Liu, Hui Yue, Yalin Tu, Yaxian Wang, Siyuan Huang, Haoran Wu, Xiaohang Long, Carol Tong, Alfred Cheng. Targeting TGF-β signaling pathway to reverse immune checkpoint blockade resistance in hepatocellular carcinoma abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P59.
Liu et al. (Thu,) studied this question.