Self-reinforcing nano-spearhead drives the efficacy of CAR-T cells against progressive triple negative breast cancer

Abstract

Despite great success of chimeric antigen receptor T (CAR-T) cells in hematological cancers, the efficacy in solid tumors is extremely restricted. Transforming growth factor-β (TGF-β) and hypoxia are key processes in the development of solid tumors, including the formation of neo-vasculature, dense extracellular matrix (ECM), and immunosuppression. TGF-β inhibition and hypoxia alleviation may be promising approaches to enhance activity of CAR-T cells in solid tumors. Therefore, a self-reinforcing nano-spearhead (BM/LP_siTGF-β NPs) is developed to collaboratively remodel tumor microenvironment (TME) through albumin-mediated tumor targeted delivery of TGF-β siRNA and the nano enzyme MnO₂. BM/LP_siTGF-β NPs efficiently eliminates ECM by down-regulation of TGF-β. Additionally, BM/LP_siTGF-β NPs also produces abundant O₂ and down-regulates HIF-α, leading to normalized vasculature and improved tumor immunosuppression. More importantly, the ECM degradation induced by BM/LP_siTGF-β NPs forms a self-reinforcing loop, further promoting greater tumor penetration of BM/LP_siTGF-β NPs and CAR-T cells. Due to robust TME remodeling capacity of BM/LP_siTGF-β NPs, the therapeutic efficacy of Mesothelin (MSLN) CAR-T cells against triple negative breast cancer (TNBC) are enhanced both in vitro and in vivo. This nano-spearhead provides a good regimen for potent TME remodeling and gives rise to enhanced CAR-T cell efficacy in TNBC treatment.