Session 3:  Cancer therapeutic innovations

Furin silencing in T cells and repression by small molecule inhibitors reverses the exhausted phenotype of tumor-infiltrating T cells and enhances anti-tumor immunity

Dysregulated expression of immune checkpoints allows cancer cells to evade immune destruction. While blocking inhibitory checkpoints is crucial in cancer immunotherapy, altered activity of regulatory factors can compromise treatment efficacy. Furin, plays a crucial role in cancer cell behavior. However, mechanisms controlling these processes and immune responses are still unclear, and the development of Furin inhibitors for therapeutic use remains unexplored. Genetic ablation of Furin in mouse T cells inhibits tumor growth and enhances overall survival when utilized in combination with anti-PD-1 and radiotherapy. Single-cell RNA sequencing (scRNAseq) analysis, identify the role of Furin T cells in regulating the expression of various immune checkpoint molecules and the infiltration of lymphoid and myeloid cells with anti-tumor activity within the tumor microenvironment (TME). Using AI-assisted virtual screening, we identified small-molecule Furin inhibitors (I0-I13), demonstrating efficacy in mouse models and patient samples. Notably, the compound I0 inhibits PD-1 expression by repressing various kinase activities in T cells. Combination of I0 with anti-PD1 and radiotherapy exhibits greater pre-clinical efficacy. This study supports the rationale for clinical testing of Furin inhibitors and establishes a foundation for further exploration of combination strategies in clinical settings.