PSMA‐Targeted Nanoparticles with PI3K/mTOR Dual Inhibitor Downregulate P‐Glycoprotein and Inactivate Myeloid‐Derived Suppressor Cells for Enhanced Chemotherapy and Immunotherapy in Prostate Cancer

Acquired drug resistance and the immunosuppressive tumor microenvironment significantly limit the efficacy of chemotherapy and immunotherapy in advanced prostate cancer. Blocking the PI3K/mTOR signaling pathway has been recently proved as a new strategy to improve sensitivity to chemotherapy and immunotherapy. Herein, glutathione (GSH)-sensitive nanoparticles (PSMA-NP/BEZ) are developed that can target prostate-specific membrane antigen (PSMA), loaded with PI3K/mTOR dual inhibitor prodrug BEZ235. BEZ235 can be released from PSMA-NP/BEZ in response to elevated GSH levels in prostate cancer tissues, inhibiting the PI3K/AKT/mTOR pathway and impairing downstream cellular functions such as cell proliferation, DNA repair, and protein synthesis. When combined with paclitaxel, PSMA-NP/BEZ could reduce drug efflux by downregulating P-glycoprotein expression in cancer cells, thus enhancing the sensitivity to chemotherapy. Furthermore, PSMA-NP/BEZ could impair the immunosuppressive functions of myeloid-derived suppressor cells and reshape the "cold" immune microenvironment in prostate cancer, enhancing immunotherapeutic efficacy and including long-term immune memory against tumor recurrence. PSMA-NP/BEZ serves a safe and promising strategy to improve the efficacy of chemotherapy and immunotherapy in advanced prostate cancer.