Abstract
Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nat. Rev. Drug Discov. 17, 887–904 (2018).
DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
Locati, M., Curtale, G. & Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol. 15, 123–147 (2020).
Jahchan, N. S. et al. Tuning the tumor myeloid microenvironment to fight cancer. Front. Immunol. 10, 1611 (2019).
Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).
Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602 (2019).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).
Kim, I. S. et al. Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nat. Cell Biol. 21, 1113–1126 (2019).
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020). This is the first study to use primary human macrophages transduced with a CAR recognizing the HER2 antigen; a phase I clinical trial using CAR-M is under way.
Advani, R. et al. CD47 Blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018). This is a phase Ib study in patients with non-Hodgkin lymphoma that showed promising activity of combining rituximab and CD47 blockade, pointing to CD47 as a novel myeloid checkpoint.
Siu, L. L. et al. First-in-class anti-immunoglobulin-like transcript 4 myeloid-specific antibody MK-4830 abrogates a PD-1 resistance mechanism in patients with advanced solid tumors. Clin. Cancer Res. 28, 57–70 (2022). This paper presents promising preliminary results observed with the MK-4830 antibody, targeting the myeloid-specific ILT4 receptor in advanced solid tumours; the mechanism of action includes reprogramming of TAMs to enhance T cell activity.
Virtakoivu, R. et al. Systemic blockade of clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors: results from a phase I/II clinical trial. Clin. Cancer Res. 27, 4205–4220 (2021).
Bottazzi, B. et al. Regulation of the macrophage content of neoplasms by chemoattractants. Science 220, 210–212 (1983). This study is the first demonstration that macrophages are recruited in tumour tissues by tumour-derived chemotactic factors, later identified as CCL2.
Bain, C. C. et al. Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat. Commun. 7, ncomms11852 (2016).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338 (2017).
Etzerodt, A. et al. Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer. J. Exp. Med. 217, e20191869 (2020).
Blériot, C., Chakarov, S. & Ginhoux, F. Determinants of resident tissue macrophage identity and function. Immunity 52, 957–970 (2020).
Gutmann, D. H. & Kettenmann, H. Microglia/brain macrophages as central drivers of brain tumor pathobiology. Neuron 104, 442–449 (2019).
Müller, A., Brandenburg, S., Turkowski, K., Müller, S. & Vajkoczy, P. Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells. Int. J. Cancer 137, 278–288 (2015).
Dumas, A. A. et al. Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment. EMBO J. 39, e103790 (2020).
Gangoso, E. et al. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell 184, 2454–2470 (2021).
Casanova-Acebes, M. et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature 595, 578–584 (2021). This study dissected the role of tissue-resident macrophages and monocyte-derived macrophages in lung cancer, showing that tissue-resident macrophages promote early epithelial–mesenchymal transition and tumour invasiveness, and a potent regulatory T cell response.
Pombo Antunes, A. R. et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat. Neurosci. 24, 595–610 (2021).
Martinez-Usatorre, A. et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci. Transl Med. 13, eabd1616 (2021).
Singhal, S. et al. Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer. Sci. Transl Med. 11, eaat1500 (2019).
Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).
Martinez, F. O. et al. Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood 121, e57–e69 (2013).
Leader, A. M. et al. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell 39, 1594–1609 (2021).
Li, H. et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell 40, 36–52 (2022).
Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018).
Dzutsev, A. et al. Microbes and cancer. Annu. Rev. Immunol. 35, 199–228 (2017).
Zhang, Q. et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma. Cancer Discov. 11, 1248–1267 (2021).
Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017).
Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).
Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765 (2017).
Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).
Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334 (2019).
Klemm, F. et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181, 1643–1660 (2020).
Friebel, E. et al. Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell 181, 1626–1642 (2020).
Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308 (2018).
Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624 (2017).
Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).
Chevrier, S. et al. An immune atlas of clear cell renal cell carcinoma. Cell 169, 736–749 (2017).
Donadon, M. et al. Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis. J. Exp. Med. 217, e20191847 (2020).
Braun, D. A. et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 39, 632–648 (2021).
Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459 (2020).
Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752 (2021).
Cortese, N., Carriero, R., Laghi, L., Mantovani, A. & Marchesi, F. Prognostic significance of tumor-associated macrophages: past, present and future. Semin. Immunol. 48, 101408 (2020).
Forssell, J. et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin. Cancer Res. 13, 1472–1479 (2007).
Malesci, A. et al. Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology 6, e1342918 (2017).
Quail, D. F. & Dannenberg, A. J. The obese adipose tissue microenvironment in cancer development and progression. Nat. Rev. Endocrinol. 15, 139–154 (2019).
Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).
Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).
Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013). This study demonstrates that the registered anti-tumour agent trabectedin has selective cytotoxicity against the monocyte–macrophage lineage, which contributes to its anti-tumour efficacy.
Di Caro, G. et al. Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy. Gut 65, 1710–1720 (2016).
Heath, O. et al. Chemotherapy induces tumor-associated macrophages that aid adaptive immune responses in ovarian cancer. Cancer Immunol. Res. 9, 665–681 (2021).
Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).
Shiao, S. L. et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell 39, 1202–1213.e6 (2021).
Singh, S. et al. FDA approval summary: lurbinectedin for the treatment of metastatic small cell lung cancer. Clin. Cancer Res. 27, 2378–2382 (2021).
Shaked, Y. The pro-tumorigenic host response to cancer therapies. Nat. Rev. Cancer 19, 667–685 (2019).
Li, J. et al. PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response. Proc. Natl Acad. Sci. USA 118, e2009290118 (2021).
Paulus, P., Stanley, E. R., Schafer, R., Abraham, D. & Aharinejad, S. Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res. 66, 4349–4356 (2006).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).
Salvagno, C. et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat. Cell Biol. 21, 511–521 (2019).
Gomez-Roca, C. A. et al. Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages. Ann. Oncol. 30, 1381–1392 (2019).
Gül, N. & van Egmond, M. Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer. Cancer Res. 75, 5008–5013 (2015).
DiLillo, D. J. & Ravetch, J. V. Fc-receptor interactions regulate both cytotoxic and immunomodulatory therapeutic antibody effector functions. Cancer Immunol. Res. 3, 704–713 (2015).
Uchida, J. et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J. Exp. Med. 199, 1659–1669 (2004).
Weng, W. K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).
Musolino, A. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J. Clin. Oncol. 26, 1789–1796 (2008).
Bibeau, F. et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J. Clin. Oncol. 27, 1122–1129 (2009).
Lapenna, A., De Palma, M. & Lewis, C. E. Perivascular macrophages in health and disease. Nat. Rev. Immunol. 18, 689–702 (2018).
Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008).
Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016).
Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016).
Stender, J. D. et al. Structural and molecular mechanisms of cytokine-mediated endocrine resistance in human breast cancer cells. Mol. Cell 65, 1122–1135 (2017).
Siersbæk, R. et al. IL6/STAT3 signaling hijacks estrogen receptor α enhancers to drive breast cancer metastasis. Cancer Cell 38, 412–423 (2020).
Cioni, B. et al. Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nat. Commun. 11, 4498 (2020).
Calcinotto, A. et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559, 363–369 (2018). This study shows that IL-23 secreted by myeloid cells acts on prostate cancer cells and promotes the development of castration-resistant prostate cancer, linking inflammatory pathways to androgen therapy.
Formenti, S. C. & Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009).
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017). A seminal review improving our understanding of the mechanisms limiting cancer immunotherapy.
Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).
Bloch, O. et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin. Cancer Res. 19, 3165–3175 (2013).
Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
Tang, H. et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J. Clin. Invest. 128, 580–588 (2018). In this paper, the relevant therapeutic target of ICB in preclinical models was PDL1 expressed by myeloid cells and not by tumour cells, suggesting that host expression of checkpoint molecules has an essential role in response and resistance.
Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).
Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).
Laba, S., Mallett, G. & Amarnath, S. The depths of PD-1 function within the tumor microenvironment beyond CD8+ T cells. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2021.05.022 (2021).
Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011). This study identifies a novel and structurally distinct member of the immunoglobulin superfamily inhibitory ligands, homologous to PDL1, produced by myeloid cells and whose blockade interferes with suppression of T cell responses.
Johnston, R. J. et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature 574, 565–570 (2019).
Rogers, B. M. et al. VISTA is an activating receptor in human monocytes. J. Exp. Med. 218, e20201601 (2021).
Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021). This work shows that tissue contexture dictates the role of macrophages in cancer given that liver tumours but not lung metastasis induced macrophage-mediated resistance to ICB.
Chow, A. et al. Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. Cancer Cell 39, 973–988 (2021).
Krishna, C. et al. Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy. Cancer Cell 39, 662–677 (2021).
Koh, M. Y., Sayegh, N. & Agarwal, N. Seeing the forest for the trees-single-cell atlases link CD8. Cancer Cell 39, 594–596 (2021).
Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
Fridlender, Z. G. et al. CCL2 blockade augments cancer immunotherapy. Cancer Res. 70, 109–118 (2010).
Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057–5069 (2014).
Peranzoni, E. et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc. Natl Acad. Sci. USA 115, E4041–E4050 (2018).
Neubert, N. J. et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl Med. 10, eaan3311 (2018).
Beltraminelli, T. & De Palma, M. Biology and therapeutic targeting of tumour-associated macrophages. J. Pathol. 250, 573–592 (2020).
Argyle, D. & Kitamura, T. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front. Immunol. 9, 2629 (2018).
Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014). Together with Pyonteck et al., these authors demonstrate that monocytes/macrophages can be targeted using small molecule inhibitors or antibodies to the CSF1 receptor, inhibiting tumour progression in preclinical models.
Pfirschke, C. et al. Macrophage-targeted therapy unlocks antitumoral cross-talk between IFNγ-secreting lymphocytes and IL12-producing dendritic cells. Cancer Immunol. Res. 10, 40–55 (2022).
Cassier, P. A. et al. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. Eur. J. Cancer 141, 162–170 (2020).
Bissinger, S. et al. Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition. Sci. Transl Med. 13, eabd4550 (2021).
Rodriguez-Garcia, A. et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat. Commun. 12, 877 (2021).
Etzerodt, A. et al. Specific targeting of CD163 mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. J. Exp. Med. 216, 2394–2411 (2019).
Reis, E. S., Mastellos, D. C., Ricklin, D., Mantovani, A. & Lambris, J. D. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5–18 (2018).
Pio, R., Ajona, D., Ortiz-Espinosa, S., Mantovani, A. & Lambris, J. D. Complementing the cancer-immunity cycle. Front. Immunol. 10, 774 (2019).
Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225–1235 (2008). This is a pioneering study showing that the generation of complement C5a in a tumour microenvironment enhances tumour growth by promoting the recruitment of MDSCs into tumours and their T cell-directed suppressive abilities.
Magrini, E. et al. Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and immunosuppression. Nat. Cancer 2, 218–232 (2021). This study systematically assessed the role of complement activation and effector pathways in preclinical sarcoma models, showing that the lectin pathway and C3a–C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.
Medler, T. R. et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell 34, 561–578 (2018).
Laskowski, J. et al. Complement factor H-deficient mice develop spontaneous hepatic tumors. J. Clin. Invest. 130, 4039–4054 (2020).
Daugan, M. V. et al. Intracellular factor H drives tumor progression independently of the complement cascade. Cancer Immunol. Res 9, 909–925 (2021).
Roumenina, L. T., Daugan, M. V., Petitprez, F., Sautès-Fridman, C. & Fridman, W. H. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).
Roumenina, L. T. et al. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunol. Res. 7, 1091–1105 (2019).
Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015). This is the first study showing that a humoral innate immunity effector molecule, PTX3, acts as an extrinsic oncosuppressor gene in mouse and human by regulating complement-dependent, macrophage-sustained, tumour-promoting inflammation.
Rubino, M. et al. Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer. Oncoimmunology 6, e1333215 (2017).
Vadrevu, S. K. et al. Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 74, 3454–3465 (2014).
Ajona, D. et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 7, 694–703 (2017).
Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).
Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017). This study proved that IL-1 represents a driver of tumour progression in human lung cancer by showing that an anti-inflammatory therapy with canakinumab targeting the IL-1β innate immunity pathway significantly reduced incident lung cancer and lung cancer mortality in a high-risk atherosclerosis population.
Garlanda, C. & Mantovani, A. Interleukin-1 in tumor progression, therapy, and prevention. Cancer Cell 39, 1023–1027 (2021).
Kaplanov, I. et al. Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation. Proc. Natl Acad. Sci. USA 116, 1361–1369 (2019).
Aggen, D. H. et al. Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model: multidimensional analyses. Clin. Cancer Res. 27, 608–621 (2021).
Wong, C. C. et al. Inhibition of IL1β by canakinumab may be effective against diverse molecular subtypes of lung cancer: an exploratory analysis of the CANTOS trial. Cancer Res. 80, 5597–5605 (2020).
Tengesdal, I. W. et al. Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion. Proc. Natl Acad. Sci. USA 118, e2000915118 (2021). This study showed that NLRP3 activation occurs in human metastatic melanoma and that it drives melanoma progression in mice by inducing IL-1β-dependent inflammation and immunosuppression, demonstrating that NLRP3 is a promising target in patients with melanoma treated with immunotherapy.
Zhang, F. et al. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers. Nat. Commun. 10, 3974 (2019).
Curtale, G., Rubino, M. & Locati, M. MicroRNAs as molecular switches in macrophage activation. Front. Immunol. 10, 799 (2019).
Zang, X. et al. Targeted delivery of miRNA 155 to tumor associated macrophages for tumor immunotherapy. Mol. Pharm. 16, 1714–1722 (2019).
Baer, C. et al. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat. Cell Biol. 18, 790–802 (2016).
Lopez-Yrigoyen, M., Cassetta, L. & Pollard, J. W. Macrophage targeting in cancer. Ann. NY Acad. Sci. 1499, 18–41 (2021).
Allavena, P., Anfray, C., Ummarino, A. & Andón, F. T. Therapeutic manipulation of tumor-associated macrophages: facts and hopes from a clinical and translational perspective. Clin. Cancer Res. 27, 3291–3297 (2021).
Beatty, G. L. et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19, 6286–6295 (2013).
Huffman, A. P., Lin, J. H., Kim, S. I., Byrne, K. T. & Vonderheide, R. H. CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity. JCI Insight 5, e137263 (2020).
Hoves, S. et al. Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J. Exp. Med. 215, 859–876 (2018).
O’Hara, M. H. et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 22, 118–131 (2021).
Ji, N. et al. Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial. Oncoimmunology 8, 1614857 (2019).
McWhirter, S. M. & Jefferies, C. A. Nucleic acid sensors as therapeutic targets for human disease. Immunity 53, 78–97 (2020).
Fitzgerald, K. A. & Kagan, J. C. Toll-like receptors and the control of immunity. Cell 180, 1044–1066 (2020).
Pettenati, C. & Ingersoll, M. A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 15, 615–625 (2018).
Sun, L. et al. Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell 39, 1361–1374 (2021).
Anfray, C. et al. Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity. J. Immunother. Cancer 9, e002408 (2021).
Frega, G. et al. Trial Watch: experimental TLR7/TLR8 agonists for oncological indications. Oncoimmunology 9, 1796002 (2020).
Márquez-Rodas, I. et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci. Transl Med. 12, eabb0391 (2020).
Kyi, C. et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin. Cancer Res. 24, 4937–4948 (2018).
Goldberg, M. S. Improving cancer immunotherapy through nanotechnology. Nat. Rev. Cancer 19, 587–602 (2019).
Irvine, D. J. & Dane, E. L. Enhancing cancer immunotherapy with nanomedicine. Nat. Rev. Immunol. 20, 321–334 (2020).
Lu, R. et al. Formulation and preclinical evaluation of a toll-like receptor 7/8 agonist as an anti-tumoral immunomodulator. J. Control. Rel. 306, 165–176 (2019).
Ribas, A. et al. Overcoming PD-1 blockade resistance with CpG-A toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov. 11, 2998–3007 (2021).
Ackerman, S. E. et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat. Cancer 2, 18–33 (2021).
Chow, L. Q. M. et al. Phase Ib trial of the toll-like receptor 8 agonist, motolimod (VTX-2337), combined with cetuximab in patients with recurrent or metastatic SCCHN. Clin. Cancer Res. 23, 2442–2450 (2017).
Ferris, R. L. et al. Effect of adding motolimod to standard combination chemotherapy and cetuximab treatment of patients with squamous cell carcinoma of the head and neck: the active8 randomized clinical trial. JAMA Oncol. 4, 1583–1588 (2018).
Frank, M. J. et al. In situ vaccination with a TLR9 agonist and local low-dose radiation induces systemic responses in untreated indolent lymphoma. Cancer Discov. 8, 1258–1269 (2018).
Karapetyan, L., Luke, J. J. & Davar, D. Toll-like receptor 9 agonists in cancer. OncoTargets Ther. 13, 10039–10060 (2020).
Li, J. K., Balic, J. J., Yu, L. & Jenkins, B. TLR agonists as adjuvants for cancer vaccines. Adv. Exp. Med. Biol. 1024, 195–212 (2017).
Vermaelen, K. Vaccine strategies to improve anti-cancer cellular immune responses. Front. Immunol. 10, 8 (2019).
Kalbasi, A. et al. Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci. Transl Med. 12, eabb0152 (2020).
Smith, M. et al. Trial watch: toll-like receptor agonists in cancer immunotherapy. Oncoimmunology 7, e1526250 (2018).
Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
Vanpouille-Box, C., Hoffmann, J. A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors- therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 18, 845–867 (2019).
Le Naour, J., Zitvogel, L., Galluzzi, L., Vacchelli, E. & Kroemer, G. Trial watch: STING agonists in cancer therapy. Oncoimmunology 9, 1777624 (2020).
Zhou, S., Kestell, P., Baguley, B. C. & Paxton, J. W. 5,6-dimethylxanthenone-4-acetic acid (DMXAA): a new biological response modifier for cancer therapy. Invest. New Drugs 20, 281–295 (2002).
Motedayen Aval, L., Pease, J. E., Sharma, R. & Pinato, D. J. Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy. J. Clin. Med. 9, 3323 (2020).
Zou, S. S. et al. Intrinsic strategies for the evasion of cGAS-STING signaling-mediated immune surveillance in human cancer: how therapy can overcome them. Pharmacol. Res. 166, 105514 (2021).
Pan, B. S. et al. An orally available non-nucleotide STING agonist with antitumor activity. Science 369, eaba6098 (2020).
Lam, K. C. et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell 184, 5338–5356 (2021).
Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).
Mantovani, A. & Longo, D. L. Macrophage checkpoint blockade in cancer - back to the future. N. Engl. J. Med. 379, 1777–1779 (2018).
Feng, M. et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat. Rev. Cancer 19, 568–586 (2019).
Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009). Together with Jaiswal, S. et al., this paper demonstrates that cancer cells with high levels of the protein CD47 have a survival advantage and avoid phagocytosis by macrophages, inspiring the generation of therapeutic inhibitors to block CD47 and its receptor SIRPα.
Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009). Together with Majeti, R. et al., this paper demonstrates that cancer cells with high levels of the protein CD47 have a survival advantage and avoid phagocytosis by macrophages, inspiring the generation of therapeutic inhibitors to block CD47 and its receptor SIRPα.
Gholamin, S. et al. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci. Transl Med. 9, eaaf2968 (2017).
Tseng, D. et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl Acad. Sci. USA 110, 11103–11108 (2013).
Ring, N. G. et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc. Natl Acad. Sci. USA 114, E10578–E10585 (2017).
Zhang, M. et al. Anti-CD47 treatment stimulates phagocytosis of glioblastoma by M1 and M2 polarized macrophages and promotes M1 polarized macrophages in vivo. PLoS ONE 11, e0153550 (2016).
Weiskopf, K. et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J. Clin. Invest. 126, 2610–2620 (2016).
Upton, R. et al. Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc. Natl Acad. Sci. USA 118, e2026849118 (2021).
van Bommel, P. E. et al. CD20-selective inhibition of CD47-SIRPα “don’t eat me” signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab. Oncoimmunology 7, e1386361 (2018).
Wang, Y. et al. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol. Immunother. 70, 365–376 (2021).
Hendriks, M. A. J. M. et al. Bispecific antibody approach for EGFR-directed blockade of the CD47-SIRPα “don’t eat me” immune checkpoint promotes neutrophil-mediated trogoptosis and enhances antigen cross-presentation. Oncoimmunology 9, 1824323 (2020).
Tian, L. et al. Targeting Fc receptor-mediated effects and the “don’t eat me” signal with an oncolytic virus expressing an anti-CD47 antibody to treat metastatic ovarian cancer. Clin. Cancer Res. 28, 201–214 (2022).
Jing, W. et al. Breast cancer cells promote CD169+ macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages. Int. Immunopharmacol. 78, 106012 (2020).
Ibarlucea-Benitez, I., Weitzenfeld, P., Smith, P. & Ravetch, J. V. Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity. Proc. Natl Acad. Sci. USA 118, e2107424118 (2021).
Festenstein, H. & Garrido, F. MHC antigens and malignancy. Nature 322, 502–503 (1986).
Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018).
Chen, H. M. et al. Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J. Clin. Invest. 128, 5647–5662 (2018).
Sharma, N., Atolagbe, O. T., Ge, Z. & Allison, J. P. LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy. J. Exp. Med. 218, e20201811 (2021).
Jensen, T. O. et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J. Clin. Oncol. 27, 3330–3337 (2009).
Lau, S. K., Chu, P. G. & Weiss, L. M. CD163: a specific marker of macrophages in paraffin-embedded tissue samples. Am. J. Clin. Pathol. 122, 794–801 (2004).
Allavena, P. et al. Engagement of the mannose receptor by tumoral mucins activates an immune suppressive phenotype in human tumor-associated macrophages. Clin. Dev. Immunol. 2010, 547179 (2010).
Chieppa, M. et al. Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J. Immunol. 171, 4552–4560 (2003).
Heinsbroek, S. E. et al. miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation. Mucosal Immunol. 9, 960–973 (2016).
Rahabi, M. et al. Divergent roles for macrophage C-type lectin receptors, dectin-1 and mannose receptors, in the intestinal inflammatory response. Cell Rep. 30, 4386–4398 (2020).
Jaynes, J. M. et al. Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses. Sci. Transl Med. 12, eaax6337 (2020).
Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000–2011 (2016).
La Fleur, L. et al. Targeting MARCO and IL37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function. Cancer Res. 81, 956–967 (2021).
Molgora, M. et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 (2017).
Eisinger, S. et al. Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by natural killer cells. Proc. Natl Acad. Sci. USA 117, 32005–32016 (2020).
Sa, J. K. et al. Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma. Genome Biol. 21, 216 (2020).
Palani, S. et al. Stabilin-1/CLEVER-1, a type 2 macrophage marker, is an adhesion and scavenging molecule on human placental macrophages. Eur. J. Immunol. 41, 2052–2063 (2011).
Viitala, M. et al. Immunotherapeutic blockade of macrophage clever-1 reactivates the CD8. Clin. Cancer Res. 25, 3289–3303 (2019). In this study, blocking Clever 1 expressed by M2-like macrophages unleashed macrophage and T cell-mediated antitumour immunity, pointing to Clever 1 as a novel ‘don’t eat me’ signal.
Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900 (2020).
Katzenelenbogen, Y. et al. Coupled scRNA-Seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872–885 (2020).
Binnewies, M. et al. Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell Rep. 37, 109844 (2021).
Turnbull, I. R. et al. Cutting edge: TREM2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).
Nguyen, P. et al. 862 Targeting PSGL-1, a novel macrophage checkpoint, repolarizes suppressive macrophages, induces an inflammatory tumor microenvironment, and suppresses tumor growth. J. Immunother. Cancer 8, https://doi.org/10.1136/jitc-2020-SITC2020.0862 (2020).
Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).
Mehla, K. & Singh, P. K. Metabolic regulation of macrophage polarization in. Cancer Trends Cancer 5, 822–834 (2019).
Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).
Guerriero, J. L. et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543, 428–432 (2017).
Ossenkoppele, G. J. et al. A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor-in patients with advanced haematological malignancies. Br. J. Haematol. 162, 191–201 (2013).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Zhao, Q. et al. 2-Deoxy-d-glucose treatment decreases anti-inflammatory M2 macrophage polarization in mice with tumor and allergic airway inflammation. Front. Immunol. 8, 637 (2017).
Wang, S. et al. Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: results of a phase II clinical trial. Clin. Cancer Res. 26, 4921–4932 (2020).
Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).
Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).
Devalaraja, S. et al. Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell 180, 1098–1114 (2020).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Oh, M. H. et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Invest. 130, 3865–3884 (2020).
Menga, A. et al. Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages. EMBO Mol. Med. 12, e11210 (2020).
Labadie, B. W., Bao, R. & Luke, J. J. Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan-kynurenine-aryl hydrocarbon axis. Clin. Cancer Res. 25, 1462–1471 (2019).
Van den Eynde, B. J., van Baren, N. & Baurain, J. F. Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma? Annu. Rev. Cancer Biol. 4, 241–256 (2020).
Hong, C. & Tontonoz, P. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13, 433–444 (2014).
Bonavita, E. et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity 53, 1215–1229 (2020). This study showed that tumour-derived PGE2 plays a key role in inhibiting NK cell-driven myeloid cell reprogramming and enabling immune evasion in mice; the signature associated with the COX2–PGE2 axis and NK cell activity predicted patient survival and response to ICB.
Porta, C. et al. Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSCs. Cancer Res. 80, 2874–2888 (2020).
Pelly, V. S. et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discov. 11, 2602–2619 (2021).
Allavena, P. et al. PLGA based nanoparticles for the monocyte-mediated anti-tumor drug delivery system. J. Biomed. Nanotechnol. 16, 212–223 (2020).
De Palma, M. et al. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14, 299–311 (2008). In this pioneering study, monocytes were transduced with the IFNA gene and used as cellular vehicles to deliver the anti-tumour cytokine IFNα to the immune microenvironment of tumours.
Shields, C. W. et al. Cellular backpacks for macrophage immunotherapy. Sci. Adv. 6, eaaz6579 (2020).
Kaczanowska, S. et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell 184, 2033–2052 (2021).
Sunseri, N., O’Brien, M., Bhardwaj, N. & Landau, N. R. Human immunodeficiency virus type 1 modified to package Simian immunodeficiency virus Vpx efficiently infects macrophages and dendritic cells. J. Virol. 85, 6263–6274 (2011).
Bobadilla, S., Sunseri, N. & Landau, N. R. Efficient transduction of myeloid cells by an HIV-1-derived lentiviral vector that packages the Vpx accessory protein. Gene Ther. 20, 514–520 (2013).
Zhang, W. et al. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix. Br. J. Cancer 121, 837–845 (2019).
Biglari, A., Southgate, T. D., Fairbairn, L. J. & Gilham, D. E. Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo. Gene Ther. 13, 602–610 (2006).
Morrissey, M. A. et al. Chimeric antigen receptors that trigger phagocytosis. Elife 7, e36688 (2018).
Sloas, C., Gill, S. & Klichinsky, M. Engineered CAR-macrophages as adoptive immunotherapies for solid tumors. Front. Immunol. 12, 783305 (2021).
Zhang, Q. W. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE 7, e50946 (2012).
Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest. New Drugs 31, 760–768 (2013).
Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).
Haag, G. M. et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer - The PICCASSO phase I trial. Eur. J. Cancer 167, 112–122 (2022).
Manji, G. A. et al. A phase I study of the combination of pexidartinib and sirolimus to target tumor-associated macrophages in unresectable sarcoma and malignant peripheral nerve sheath tumors. Clin. Cancer Res. 27, 5519–5527 (2021).
Lin, C. Phase I study of BLZ945 alone and with spartalizumab (PDR001) in patients (pts) with advanced solid tumors. Cancer Res. 80 (Suppl. 16), CT171 (2020).
Razak, A. R. et al. Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. J. Immunother. Cancer 8, e001006 (2020).
Fisher, G. A. et al. A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients. JCO Gastointestinal Cancers Symp. 38 (Suppl. 4), 114 (2020).
Marquez-Rodas, I. et al. Combination of radiomic and biomarker signatures as exploratory objective in a phase II trial with intratumoral BO-112 plus pembrolizumab for advanced melanoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.2021.39.15_suppl.TPS9586 (2021).
Sharma, M. et al. Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients (pts) with advanced HER2-expressing solid tumors. J. Clin. Oncol. 39 (Suppl. 15), 2549 (2021).
Finocchiaro, G. et al. A phase I-IIa study of genetically modified Tie-2 expressing monocytes in patients with glioblastoma multiforme (TEM-GBM Study). J. Clin. Oncol. 39 (Suppl. 15), 2532 (2021).
Guilliams, M., Mildner, A. & Yona, S. Developmental and functional heterogeneity of monocytes. Immunity 49, 595–613 (2018).
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).
Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2015).
Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).
Zhang, B. et al. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumor immunity. Nature 599, 471–476 (2021).
Scala, S. & Aiuti, A. In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions. Blood Adv. 3, 1916–1924 (2019).
Jaillon, S. et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat. Rev. Cancer 20, 485–503 (2020).
Güç, E. & Pollard, J. W. Redefining macrophage and neutrophil biology in the metastatic cascade. Immunity 54, 885–902 (2021).
Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).
Ma, R. Y. et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. 217, e20191820 (2020).
Bieniasz-Krzywiec, P. et al. Podoplanin-expressing macrophages promote lymphangiogenesis and lymphoinvasion in breast cancer. Cell Metab. 30, 917–936 (2019).
Singh, R. & Choi, B. K. Siglec1-expressing subcapsular sinus macrophages provide soil for melanoma lymph node metastasis. Elife 8, e48916 (2019).
Colombo, N. et al. Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int. J. Cancer 51, 42–46 (1992).
Marchesi, F., Piemonti, L., Mantovani, A. & Allavena, P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor. Rev. 21, 77–82 (2010).
Obradovic, A. et al. Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages. Cell 184, 2988–3005 (2021).
Combes, A. J. et al. Discovering dominant tumor immune archetypes in a pan-cancer census. Cell 185, 184–203 (2022).
Cheng, S. et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792–809 (2021).
Raghavan, S. et al. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 184, 6119–6137 (2021).
Acknowledgements
The research leading to the results here reviewed has received funding from Associazione Italiana Ricerca Cancro (AIRC): AIRC 5×1000 21147 to A.M.; AIRC-IG 23465 to A.M.; AIRC-IG 21714 to C.G.; the Italian Ministry of Health (Ricerca Finalizzata: RF-2019-12369142 to F.M.; RF-2013-02355470 to C.G.) and EuroNanoMed III-2-INTRATARGET project (PCIN-2017-129/AEI) to P.A. The funding agency had no role in the preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
The authors have equally contributed to this review.
Corresponding author
Ethics declarations
Competing interests
A.M. has been a recipient of commercial research grants from Sigma Tau, Roche, Novartis, Compugen and Efranat, and has been a consultant/advisory board member/lecturer for Novartis, Roche, Ventana, Pierre Fabre, Verily, Abbvie, BMS, J&J, Compugen, Imcheck, Macrophage Therapeutics, AstraZeneca, Biovelocita, BG Fund, Third Rock, Verseau Therapeutics and Olatec Therapeutics. C.G. and P.A. are recipients of research grants from Imcheck and Macrophage Therapeutics. A.M. and C.G. are inventors of patents related to PTX3 and other innate immunity molecules. A.M., C.G. and P.A. receive royalties for reagents related to innate immunity.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks Jeffrey Pollard, Michele De Palma, and the other, anonymous, reviewer for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
Myeloid Therapeutics technology platforms: https://www.myeloidtx.com/our-science
Glossary
- Myelomonocytic cells
-
Haematopoietic cells, including monocytes, macrophages and monocyte-derived dendritic cells.
- Desmoplastic reaction
-
A dense, fibrous tissue that is formed in some tumours secondary to the tissue repair response orchestrated by inflammatory cells.
- Regulatory T cells
-
A specialized population of T cells that suppress the activation of other T cells and maintain peripheral tolerance to self-antigens.
- Polarized type 2 adaptive immune responses
-
An adaptive immune response induced by cytokines from T helper 2 cells, such as IL-4, IL-5 and IL-13, and characterized by alternative macrophage activation that is important for tissue repair and fibrosis.
- Coelomic cavities
-
They include pleural, peritoneal and pericardial cavities that originate during embryogenesis in the gastrulation phase. These cavities are lined by specialized mesodermal cells called mesothelium.
- Inflammasome
-
A critical inflammatory component, composed of an intracellular oligomeric protein complex. Its activation by both pathogen and danger signals results in the assembly of the complex and leads to caspase-dependent cleavage of IL-1 and IL-18 precursors.
- Scavenger receptors
-
A heterogeneous family of cell-surface receptors expressed on phagocytes that allow recognition of pathogen-related and danger-associated molecular moieties of various nature (such as sugars and modified lipoproteins), instrumental for the defence against infections and tissue damage.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mantovani, A., Allavena, P., Marchesi, F. et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov 21, 799–820 (2022). https://doi.org/10.1038/s41573-022-00520-5
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41573-022-00520-5
This article is cited by
-
Synergistic Ferroptosis–Immunotherapy Nanoplatforms: Multidimensional Engineering for Tumor Microenvironment Remodeling and Therapeutic Optimization
Nano-Micro Letters (2026)
-
Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression
Biomarker Research (2025)
-
CD47 antibody-armed oncolytic adenovirus promotes chimeric antigen receptor macrophage phagocytosis and antitumor immunity
Experimental Hematology & Oncology (2025)
-
Harnessing myeloid cells in cancer
Molecular Cancer (2025)
-
Macrophage-derived exosomes in cancer: a double-edged sword with therapeutic potential
Journal of Nanobiotechnology (2025)
