Abstract
In the past decade, substantial advances have been made in understanding the biology of tumour-associated macrophages (TAMs), and their clinical relevance is emerging. A particular aspect that is becoming increasingly clear is that the interaction of TAMs with cancer cells and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. Therefore, manipulation of TAMs could enable improved disease control in a substantial fraction of patients across a large number of cancer types. In this Review, we examine the diversity of TAMs in various cancer indications and how this heterogeneity is being revisited with the advent of single-cell technologies, and then explore the current knowledge on the functional roles of different TAM states and the prognostic and predictive value of TAM-related signatures. We also review agents targeting TAMs that are currently being or will soon be tested in clinical trials, and how manipulations of TAMs can improve existing anticancer treatments. Finally, we discuss how TAM-targeting approaches could be further integrated into routine clinical practice, considering a precision oncology approach and viewing TAMs as a dynamic population that can evolve under treatment pressure.
Key points
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Tumour-associated macrophages (TAMs) are phenotypically and functionally diverse; therefore, some can promote tumour progression whereas others can exhibit antitumour activity.
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Some TAM states have prognostic value because their abundance is associated with distinct clinical outcomes, as is the case for TAM states in patients with melanoma and lung, colorectal, ovarian, pancreatic, stomach and kidney cancers.
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Some TAM states are associated with response to treatment, or lack thereof, as demonstrated in seminal studies involving patients with breast cancer, renal cell carcinoma and melanoma.
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Not all tumour-promoting TAMs have M2-like phenotypes, thus highlighting the importance of defining TAM states beyond the M1/M2 dichotomy.
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The diversity of TAMs suggests different possibilities for exploiting particular subsets for therapeutic purposes; as a result, an arsenal of macrophage-targeted agents are currently being tested in the clinic.
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With the integration of single-cell RNA sequencing and other omics in therapeutic decision-making processes, the inclusion of TAM data in precision oncology molecular tumour boards could become routine practice.
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Change history
06 April 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41571-022-00632-2
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Acknowledgements
M.J.P. receives support from the ISREC Foundation, Ludwig Cancer Research, and NIH grants P01-CA240239 and R01-CA218579. O.M. receives support from the ISREC Foundation, the Ludwig Cancer Research, the Swiss National Science Foundation (SNSF) 31003A_176168, the Swiss National Cancer Ligue KFS-5034-02-2020, the Swiss Personalized Health Network (SPHN), and the Personalized Health and Related Technologies (PHRT). D.M. receives support from the ISREC Foundation, Association Frédéric Fellay, Ernst and Lucie Schmidheiny Foundation, Fondation Dr Henri Dubois-Ferrière Dinu Lipatti (DFDL), Ligue Genevoise contre le cancer, Personalized Health and Related Technologies (PHRT) ETH fund, Swiss Bridge Foundation, and Swiss Innovation Agency (Innosuisse).
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M.J.P. has been a consultant for Aileron Therapeutics, AstraZeneca, Cygnal Therapeutics, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, Merck, Siamab Therapeutics, Third Rock Ventures and Tidal. O.M. has been a consultant for Amgen, BMS, GSK, MSD, Novartis, Pierre Fabre and Roche, and has received research support from Amgen, BMS, MSD, Neracare and Pierre Fabre. D.M. is an inventor on patents related to CAR T cell therapy, filed by the University of Pennsylvania and the University of Geneva, and has been a consultant for Limula Therapeutics and MPC Therapeutics.
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Pittet, M.J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat Rev Clin Oncol 19, 402–421 (2022). https://doi.org/10.1038/s41571-022-00620-6
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DOI: https://doi.org/10.1038/s41571-022-00620-6
