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
Fei Xia, Yuqian Lu, Zipeng Gong, Qingchao Tu, Shuntao Liang, Chen Wang, HaiLu Yao, Lin Zhong, Yuanfeng Fu, Pengbo Guo, Yichong Hou, Xinyu Zhou, Lili Zou, Licheng Gan, Weiqi Chen, Jiawei Yan, Junzhe Zhang, Huanhuan Pang, Yuqing Meng, Qiaoli Shi, Pan Chen, Xiaomei Tao, Jigang Wang, Qingfeng Du, Chong Qiu
Abstract
ABSTRACT 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 Mn 2+ 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 Mn 2+ (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.