Modulation of the intestinal microbiome and reversal of the immunosuppressive microenvironment by nanoparticles for chemoimmunotherapy in prostate cancer.

INTRODUCTION

Prostate cancer (PCa), a "cold" tumor with an immunosuppressive microenvironment, exhibits poor sensitivity to immunotherapies, limiting treatment efficacy. Chemotherapeutics often cause intestinal injury and disrupt gut microbiota, further impairing chemoimmunotherapy outcomes. Modulating gut microbiota to reverse immunosuppression represents a potential strategy to enhance PCa treatment.

OBJECTIVES

To develop a novel therapeutic strategy using nanomedicine to regulate intestinal flora, thereby reversing the immunosuppressive microenvironment and improving chemoimmunotherapy efficacy in PCa.

METHODS

Cabazitaxel (CBZ)-loaded, folic acid (FA)-modified pH/ROS dual-responsive nanoparticles (CBZ/FA-CA-OCD NPs) were fabricated. In vitro and in vivo experiments evaluated NPs accumulation, cellular internalization (via FA-mediated endocytosis), drug release, intestinal mucosal injury, and tumor growth inhibition. Gut microbiota modulation (e.g., Lachnospiraceae, Firmicutes, Muribaculaceae, Bacteroidota) and CD4+/CD8+ T-cell infiltration were assessed. Fecal microbiota transplantation (FMT) validated microbiota-mediated immune effects.

RESULTS

The CBZ/FA-CA-OCD NPs accumulated in PCa tissues were internalized by PC-3/LNCaP cells and released CBZ in acid/ROS microenvironments to inhibit tumor growth. Compared to free CBZ, NPs attenuated intestinal injury, modulated microbiota (increased Lachnospiraceae/Firmicutes, decreased Muribaculaceae/Bacteroidota), and enhanced anti-PD-1 efficacy by increasing CD4+/CD8+ T-cell infiltration. FMT confirmed that microbiota from NP-treated mice promoted T-cell infiltration in tumors.

CONCLUSION

CBZ/FA-CA-OCD NPs improve PCa chemoimmunotherapy by regulating gut microbiota, reversing immunosuppression, and enhancing T-cell infiltration. This nanomedicine-based strategy provides a promising approach to boost PCa treatment outcomes.