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Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance., (© 2021. The Author(s).)

Background: Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments., Methods: TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis., Results: Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4 + and CD8 + T cells, accompanied by a reduction of immunosuppressive CD206 + TAMs and FOXP3 + /CD4 + T cells. The depletion of both CD4 + and CD8 + T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway., Discussion: These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nowadays, it is well accepted that inflammation is a critical player in cancer, being, in most cases, the main character of the process. Different types of tumor arise from sites of infection or chronic inflammation. This non-resolving inflammation is responsible for tumor development at different levels: it promotes tumor initiation, as well as tumor progression, stimulating both tumor growth and metastasis. Environmental factors, lifestyle and infections are the three main triggers of chronic immune activation that promote or increase the risk of many different cancers. In this review, we focus our attention on tumor onset; in particular, we summarize the knowledge about the cause and the mechanisms behind the inflammation-driven cancer development.

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor-Associated Macrophages (TAMs) acquire an immune-suppressive and tumor-promoting phenotype. With the aim to re-educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor-Conditioned Macrophages (TC-Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC-Mϕ respond differently from conventional M2-polarized macrophages. Upon stimulation with IMQ, TC-Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC-Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL-1β and IL-6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC-Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC-Mϕ is superior than IMQ in terms of macrophage re-education toward antitumor effectors., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The engineering of new nanomedicines with ability to target and kill or re-educate Tumor Associated Macrophages (TAMs) stands up as a promising strategy to induce the effective switching of the tumor-promoting immune suppressive microenvironment, characteristic of tumors rich in macrophages, to one that kills tumor cells, is anti-angiogenic and promotes adaptive immune responses. Alternatively, the loading of monocytes/macrophages in blood circulation with nanomedicines, may be used to profit from the high infiltration ability of myeloid cells and to allow the drug release in the bulk of the tumor. In addition, the development of TAM-targeted imaging nanostructures, can be used to study the macrophage content in solid tumors and, hence, for a better diagnosis and prognosis of cancer disease. The major challenges for the effective targeting of TAM with nanomedicines and their application in the clinic have already been identified. These challenges are associated to the undesirable clearance of nanomedicines by, the mononuclear phagocyte system (macrophages) in competing organs (liver, lung or spleen), upon their intravenous injection; and also to the difficult penetration of nanomedicines across solid tumors due to the abnormal vasculature and the excessive extracellular matrix present in stromal tumors. In this review we describe the recent nanotechnology-base strategies that have been developed to target macrophages in tumors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)