Cancer Immunotherapy Based on the Bidirectional Reprogramming of the Tumor Microenvironment by a “Brakes Off/ Step on the Accelerator” Core-Shell Manganese Phosphate/siPD-L1 Modulator

The insufficient infiltration and functional inhibition of CD8⁺ T cells due to tumor microenvironment (TME) are considered enormous obstacles to anti-tumor immunotherapy. Herein, a pH-responsive core-shell manganese phosphate nanomodulator co-loading siPD-L1 and Mn²⁺ into nanoparticles coated with hyaluronic acid was prepared, which was aimed at the bidirectional reprogramming the tumor microenvironment: (1) “Brakes off,” restoring CD8⁺ T cells function by siPD-L1 knockdowning PD-L1 expression of tumor cells; (2) “Step on the accelerator,” promoting CD8⁺ T cells infiltration in tumors tissue based on the multidimensional immune effects of Mn²⁺ (immunogenic cell death induced the enhancing cGAS-STING pathway, the proliferation and maturation of relative immune cells). Additionally, this strategy could induce macrophage polarization and inhibit the regulatory T cells in tumor site. This work provided a manganese phosphate nanomodulator to reprogram the immune TME for an enhanced comprehensive anti-tumor effect of triple negative breast cancer, which offers a robust method for tumor immunotherapy in future clinical applications.