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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.
Yin et al. (Mon,) studied this question.