Multi-level ROS regulation to activate innate and adaptive immune therapies

Reprogramming the immunosuppressive tumor microenvironment (TME) to boost CD8+ T cell infiltration is crucial for anti-tumor immunotherapy. In this study, a bionic nanoplatform (VGRM) based on a two-dimensional vanadium carbide (MXene) carrying glucose oxidase (GOx) and CRISPR/Cas9 was constructed, which enabled a cascade reaction that amplified the generation of reactive oxygen species (ROS) while depleting glutathione (GSH) by combining MXenzyme and natural enzymes. The CRISPR/Cas9 system could reduce the expression of MTH1, depress tumor cells’ self-defense against oxidative stress and thus significantly enhance the therapeutic effect of ROS. Additionally, the excellent NIR-II photothermal performance endowed VGRM with photoacoustic imaging (PA) and photothermal therapy (PTT) capabilities. The enhanced oxidative stress and photothermal killing ability could activate the cGAS/STING innate immune pathway, induce immunogenic cell death (ICD), and at the same time reverse the immunosuppressive TME, which promoted CD8+ T cells infiltration, and thereby inhibiting tumor proliferation. Meanwhile, antigen-activated memory T cells (adaptive immunity) could suppress tumor recurrence and metastasis effectively. This study provides a novel strategy for the combined application of MXene and gene editing therapy in modulating the tumor immune microenvironment.