Macrophage Membrane-Coated Nanomedicine Enhances Cancer Immunotherapy by Activating Macrophages and T Cells.

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.