Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition <i>in situ</i> to achieve highly efficient radioimmunotherapy of triple negative breast cancer.

Abstract

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer (TNBC) is largely limited by the complicated tumor microenvironment (TME) and its immunosuppressive state. Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy. Therefore, we designed and synthesized a tellurium (Te)-driven maple leaf manganese carbonate nanotherapeutics (MnCO₃@Te) by gas diffusion method, but also provided a chemical catalytic strategy <i>in situ</i> to augment ROS level and activate immune cells for improving cancer radioimmunotherapy. As expected, with the help of H₂O₂ in TEM, MnCO₃@Te heterostructure with reversible Mn³⁺/Mn²⁺ transition could catalyze the intracellular ROS overproduction to amplify radiotherapy. In addition, by virtue of the ability to scavenge H⁺ in TME by carbonate group, MnCO₃@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes (STING) pathway activation, resulting in remodeling immuno-microenvironment. As a result, MnCO₃@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis <i>in vivo</i>. Collectively, these findings indicate that MnCO₃@Te as an agonist, successfully overcome radioresistance and awaken immune systems, showing promising potential for solid tumor radioimmunotherapy.