Transcriptional regulation of T cell exhaustion in immune checkpoint blockade resistance at single-cell resolution [ex vivo-scATAC]

Tumor-specific CD8+ T lymphocytes are crucial for anti-cancer immunity but can lose cytotoxic function in the immunosuppressive tumor microenvironment. Immune checkpoint blockades (ICB), like anti-PD-1 therapy, enhance and prolong anti-tumor T cell responses. Despite its widespread clinical use, resistance to ICB develops in some patients, characterized by the proliferation of exhausted T cell (Tex). Here, we establish two single-cell murine hepatocellular carcinoma (HCC) models to explore regulatory network in Tex with ICB resistance. We uncover distinct T cell compositions, including both early and terminal Tex subsets, following prolonged ICB treatment, and reveal the differentiation trajectory of Tex subsets. Finally, we not only identify transcription factor Runx2 and its downstream targets as contributors to T cell exhaustion in both models, but discover ICB response correlates to Runx2 level in human tumor-infiltrating lymphocytes. These findings elucidate Runx2 regulates T cell exhaustion in response to prolonged ICB treatment, influencing ICB effICBency, and suggest potential targets for combination therapy alongside ICB in HCC.