Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine‐Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles

T cell dysfunction‐induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It is crucial to innovatively reverse the T cell dysfunction for improving GBM immunotherapy. Herein, T cell dysfunction is remarkably reversed and immunotherapy of GBM is boosted by repurposing the U. S. Food and Drug Administration‐approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS‐J@CM/6 NPs). The PX is successfully applied to abrogate T cell sequestration in the bone marrow of GBM‐bearing mice and increase their infiltration in tumor. The biomimetic NPs are composed of ultrasmall Cu2−xSe NPs, JQ1, and tumor cell membrane modified with CD6, and are efficiently delivered into tumor through the specific interactions between CD6 and activated leukocyte cell adhesion molecule. They ameliorate the T cell dysfunction through the double roles of loaded JQ1, which simultaneously decreases the expression of PD‐1 and TIM‐3 on T cells, and the expression of PD‐L1 on tumor cells. The NP also induces the immunogenic cell death of tumor cells to activate immune response. The synergistic roles of PX and biomimetic CS‐J@CM/6 NPs notably enhance the survival of GBM‐bearing mice. This work provides new insights into tumor immunotherapy by repurposing “old drugs” with advanced NPs. Reversing T cell dysfunction to significantly boost glioblastoma immunotherapy is achieved by repurposing “old drug” paroxetine (PX) with Cu2−xSe‐based biomimetic nanoparticles. PX can release the sequestrated T cells in the bone marrow to increase their amounts and infiltration in tumor. Biomimetic nanoparticles can simultaneously reduce the expressions of immune checkpoints on tumor cells and T cells.