Macrophage Membrane-Coated Nanomedicine Enhances Cancer Immunotherapy by Activating Macrophages and T Cells
Yongmei Zhao, Lulu X Pei, Baolin Liu, Zhuo Mao, Yingyi Niu, Siqi Li, Meiqing Yang, Wenqian Liu, Hongde Hai, Y. Luo, Tianqing Liu
Abstract
Cancer immunotherapy has transformed malignancy treatment, but the tumor microenvironment (TME) presents significant obstacles. PD-1 blockade therapy, while widely used, faces issues such as resistance, adverse events, and limited predictive biomarkers. Therefore, novel therapeutic strategies are needed to enhance their efficacy and safety. Tumor-associated macrophages (TAMs), often exhibiting an anti-inflammatory M2 phenotype, contribute to poor prognoses and treatment resistance. Targeting TAMs to repolarize them to a pro-inflammatory M1 state can alleviate immunosuppression and enhance T cell-mediated antitumor responses. TMP195, a class IIa histone deacetylase inhibitor, has shown potential in reprogramming TAMs and synergizing with anti-PD-1 antibodies, although clinical application challenges exist. This study aimed to enhance the PD-1 blockade immunotherapy effectiveness by activating tumor-killing macrophages and T cells using biomimetic nanomedicines. A novel macrophage cell membrane-coated PLGA nanoparticle loaded with small molecule inhibitor, TMP195 (M1@PLGA-PEG-TMP195), was designed, prepared, and characterized. This macrophage membrane-coated PLGA nanoparticle delivery system had good drug loading and cancer cell targeting ability. This approach repolarized TAMs to M1 phenotypes and, combined with PD-1 inhibitors, achieved synergistic cancer treatment effects, improving therapeutic efficacy and inhibiting breast cancer growth and metastasis.