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.