RESUMO
Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.
Assuntos
Imidazóis , Imunoterapia , Manose , Camundongos Endogâmicos C57BL , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Macrófagos Associados a Tumor , Animais , Imidazóis/administração & dosagem , Imidazóis/química , Receptor 8 Toll-Like/agonistas , Imunoterapia/métodos , Receptor 7 Toll-Like/agonistas , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Manose/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Feminino , Humanos , Glicoproteínas de MembranaRESUMO
Cancer immunotherapy is a groundbreaking strategy that has revolutionized the field of oncology compared to other therapeutic strategies, such as surgery, chemotherapy, or radiotherapy. However, cancer complexity, tumor heterogeneity, and immune escape have become the main hurdles to the clinical application of immunotherapy. Moreover, conventional immunotherapies cause many harmful side effects owing to hyperreactivity in patients, long treatment durations and expensive cost. Nanotechnology is considered a transformative approach that enhances the potency of immunotherapy by capitalizing on the superior physicochemical properties of nanocarriers, creating highly targeted tissue delivery systems. These advantageous features include a substantial specific surface area, which enhances the interaction with the immune system. In addition, the capability to finely modify surface chemistry enables the achievement of controlled and sustained release properties. These advances have significantly increased the potential of immunotherapy, making it more powerful than ever before. In this review, we introduce recent nanocarriers for application in cancer immunotherapy based on strategies that target different main immune cells, including T cells, dendritic cells, natural killer cells, and tumor-associated macrophages. We also provide an overview of the role and significance of nanotechnology in cancer immunotherapy.