Integrated single-cell and spatial transcriptomic profiling reveals that CD177⁺ Tregs enhance immunosuppression through apoptosis and resistance to immunotherapy in hepatocellular carcinoma

Regulatory T cells (Tregs), an immunosuppressive subpopulation of CD4⁺ T cells, are prevalent in tumor tissues, where they impede effective antitumor immune responses and represent potential targets for immunotherapy. However, targeting tumor-infiltrating Treg cells (TiTregs) remains challenging. In this study, we identified CD177 as a biomarker specifically expressed in TiTregs but not in adjacent or peripheral Treg cells through single-cell transcriptome sequencing combined with a stringent screening strategy. These CD177⁺ TiTregs exhibited distinct transcriptional profiles characterized by enhanced immunosuppressive capabilities and were correlated with poor patient prognosis. Mechanistically, the apoptosis-related transcription factor REL drove the differentiation of CD177⁺ TiTregs, accompanied by apoptosis and enhanced immunosuppression. Furthermore, using a CD177 Treg conditional knockout mouse model, we demonstrated that inhibiting CD177 in Tregs significantly impaired their immunosuppressive function and inhibited the progression of hepatocellular carcinoma (HCC) in vitro. Our results underscore the critical role of CD177⁺ TiTregs in cancer immunology and highlight their potential as novel therapeutic targets in HCC.