Abstract
The tumor microenvironment (TME) plays a central role in regulating antitumor immune responses. As an important part of the TME, alternatively activated type 2 (M2) macrophages drive the development of primary and secondary tumors by promoting tumor cell proliferation, tumor angiogenesis, extracellular matrix remodeling and overall immunosuppression. Immunotherapy approaches targeting tumor-associated macrophages (TAMs) in order to reduce the immunosuppressive state in the TME have received great attention. Although these methods hold great potential for the treatment of several cancers, they also face some limitations, such as the fast degradation rate of drugs and drug-induced cytotoxicity of organs and tissues. Nanomedicine formulations that prevent TAM signaling and recruitment to the TME or deplete M2 TAMs to reduce tumor growth and metastasis represent encouraging novel strategies in cancer therapy. They allow the specific delivery of antitumor drugs to the tumor area, thereby reducing side effects associated with systemic application. In this review, we give an overview of TAM biology and the current state of nanomedicines that target M2 macrophages in the course of cancer immunotherapy, with a specific focus on nanoparticles (NPs). We summarize how different types of NPs target M2 TAMs, and how the physicochemical properties of NPs (size, shape, charge and targeting ligands) influence NP uptake by TAMs in vitro and in vivo in the TME. Furthermore, we provide a comparative analysis of passive and active NP-based TAM-targeting strategies and discuss their therapeutic potential.
Highlights
In the past decades, cancer has been the leading cause of death worldwide
MacParland et al measured the uptake of 100-micrometer-sized AuNPs by different macrophage subtypes, and the results showed that M2c macrophages had the strongest affinity for ingesting AuNPs, followed by M2 macrophages and M1 macrophages, while monocytes had the weakest affinity for NPs [199]
Another approach focused on repolarizing Tumor-Associated Macrophages (TAMs) to antitumor M1 macrophages by administration of redox/pH dual-responsive nanovectors encapsulating with polyethylene glycol (PEG)-PLL copolymers/galactose-functionalized n-butylamine-poly(l-lysine)-b-poly(l-cysteine) polypeptides (GLC) for delivery of miR155. miR155 had previously been shown to significantly attenuate the cytokine production in TAMs via targeting C/EBPβ [240] and repolarized protumoral [240] and re-polarized pro-tumoral M2 TAMs into antitumor M1 macrophages in vitro [241]
Summary
Cancer has been the leading cause of death worldwide. traditional therapies including surgery, radiotherapy and chemotherapy have reduced the incidence of cancer-related deaths, they lack selectivity towards tumor cells [1]. PLGA is one of the most successfully developed polymers, and has been widely used in the encapsulation and targeted delivery of therapeutic agents to cancer cells to enhance the effect of anticancer therapy [22,23]. The TME has become a target of NP-based delivery systems aiming to prevent tumor progression and survival, to “re-educate” immunosuppressive M2 TAMs towards the M1 type with antitumor properties and to raise an antitumor immune response [7,8,9,30,31]. Circulating monocyte precursors [36], more recently it was shown that several organs harbor embryonic-derived populations of resident macrophages that maintain and selfrenew throughout adulthood [33,37,38] These tissue-resident macrophages include brain microglia, alveolar, pancreatic, peritoneal, splenic, kidney and gut macrophages, as well as Langerhans and Kupffer cells [33,37] (Figure 2A). TAMs further support tumor malignancy and metastasis by enhancing the invasion and extravasation ability of tumor cells, inhibiting antigen presentation, as well as stimulating tumor relapse after chemotherapy [41,42,43]
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