Boost Infiltration and Activity of T Cells via Inhibiting Ecto-5′-nucleotidase (CD73) Immune Checkpoint to Enhance Glioblastoma Immunotherapy

The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu_2-<i>x</i>Se nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu²⁺) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(<i>N</i>,<i>N</i>-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8⁺ T and CD4⁺ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.