Myeloid cells are the most abundant immune components of the tumour microenvironment, where they have a variety of functions, ranging from immunosuppressive to immunostimulatory roles. The myeloid cell compartment comprises many different cell types, including monocytes, macrophages, dendritic cells and granulocytes, that are highly plastic and can differentiate into diverse phenotypes depending on cues received from their microenvironment. In the past few decades, we have gained a better appreciation of the complexity of myeloid cell subsets and how they are involved in tumour progression and resistance to cancer therapies, including immunotherapy. In this Review, we highlight key features of monocyte and macrophage biology that are being explored as potential targets for cancer therapies and what aspects of myeloid cells need a deeper understanding to identify rational combinatorial strategies to improve clinical outcomes of patients with cancer. We discuss therapies that aim to modulate the functional activities of myeloid cell populations, impacting their recruitment, survival and activity in the tumour microenvironment, acting at the level of cell surface receptors, signalling pathways, epigenetic machinery and metabolic regulators. We also describe advances in the development of genetically engineered myeloid cells for cancer therapy.
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S.G. is supported by the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award and Clinic and Laboratory Integration Program Award. P.S. is a member of the Parker Institute for Cancer Immunotherapy.
P.S. consults for and/or has equity in Jounce, Neon, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, Lava Therapeutics, Achelois, Hummingbird, Earli, Phenomics, Constellation, Glympse and Oncolytics. The remaining authors declare no competing interests.
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- Immune checkpoint therapy
(ICT). A type of cancer immunotherapy targeting T cell checkpoint molecules and their ligands, such as CTLA4, PD1 and programmed cell death ligand 1 (PDL1), to improve T cell-mediated antitumour immunity.
- Adoptive T cell therapy
A form of immunotherapy involving autologous or allogeneic transfer of engineered T cells into patients to efficiently recognize and eliminate cancer cells.
- Cancer–immunity cycle
A term coined by Ira Mellman and Daniel Chen in 2013 to describe the stepwise process of events by which the immune system detects and eliminates cancer cells in the body.
- Targeted therapy
A mode of therapy involving antagonism of pathways specifically associated with cancer cells to preferentially destroy tumour cells.
- Monocyte/macrophage lineage
The lineage of immune cells derived from common myeloid progenitors of the haematopoietic stem cell system and that differentiate into monocytes that mature into macrophages and their subsets.
- Leukocyte immunoglobulin-like receptor subfamily B member 1
(LILRB1). A member of one of the five major LILRB families (LILRB1–LILRB5). LILRB1 and LILRB2 interact with classical and non-classical HLA molecules, whereas LILRB3–LILRB5 are orphan receptors. Although not fully characterized, LILRB5 may bind β2-microglobulin-free heavy chains of HLA-B27.
- Epigenetic machinery
A group of proteins that regulate gene expression without altering the DNA sequence. This process is dynamically regulated by DNA methylation, histone post-translational modifications, promoter–enhancer interactions, non-coding RNAs and chromatin remodelling complexes.
A form of phagocytosis by which apoptotic cells are removed.
A process that removes dysfunctional components of a cell through a lysosome-dependent mechanism. Certain subsets of myeloid cells rely on autophagy to promote immunosuppression.
- Primary resistance
A term used to define complete therapy resistance in cancer due to inherent characteristics within the tumour cells.
- Adaptive or secondary resistance
A term used to define tumours that initially respond to therapy but eventually develop resistance to it.
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Goswami, S., Anandhan, S., Raychaudhuri, D. et al. Myeloid cell-targeted therapies for solid tumours. Nat Rev Immunol 23, 106–120 (2023). https://doi.org/10.1038/s41577-022-00737-w
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