A novel combination for in vivo breast cancer treatment: TAK1 inhibition combined with metformin and Lentinula edodes compounds synergistically reinvigorates CD8+ T Cells.

BACKGROUND: Breast cancer (BC) is the most prevalent cancer among women, and retrieving the anti-tumor function of the immune system seems a promising treatment approach for its crucial role in combating cancer cells. In this study, we evaluated the impact of a combination therapy containing a TAK1 inhibitor, Takinib (Tak), a metabolic regulator, Metformin (Met), and an immunostimulant, Lentinula edodes mycelia extract (LEME) on enhancing the immune system's anti-tumor activity in BALB/c mice bearing triple-negative breast cancer (TNBC).

METHODS: BALB/c mice were used to induce TNBC tumors and evaluate tumor growth inhibition. The number of CD8+ CD28+ T cells was determined by immunofluorescence assay, the expression of MUC1 protein was assessed by Western blot, while the expression of TOX, NR4A1, and TIM-3 genes was evaluated by real-time PCR in mouse-derived tumor tissues. MTT assay was performed on different BC cell lines to assess cell viability.

RESULTS: Molecular docking results revealed significant interactions between Tak and Met with TOX and NR4A1. The combination treatments of Tak, Met, and LEME significantly decreased tumor volume/weight in mice and also significantly increased the number of infiltrated CD8+ CD28+ T cells, reduced MUC-1 protein expression, and decreased the expression of TOX, NR4A1, and TIM-3 genes in mouse tumor tissue. Tak, Met, and their combination significantly decreased the cell viability of different BC cell lines.

CONCLUSION: This study suggests that the Tak-Met-LEME combination treatments may inhibit BC progression by increasing CD8+ CD28+ T cell population in tumor tissue and decreasing tumor progression.