Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity.
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Acknowledgements
The authors acknowledge F. Ginhoux for insightful feedback on the manuscript. The authors also acknowledge the following funding sources. C.Y.M. is supported by National Institutes of Health (NIH) grant F30CA287638. R.M. is supported by the 2021 AACR-AstraZeneca Immuno-oncology Research Fellowship (21-40-12-MATT) and by the Portuguese Foundation for Science and Technology (2023.15874.PEX). D.P. is supported by Damon Runyon Rachleff Innovator Award, an NIH DP2 New Innovator Award (1DP2AI177905-0) and the Blavatnik Foundation. M.M. is partially supported by NIH grants CA257195, CA254104 and CA154947.
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C.Y.M., M.B., R.M. and M.D.P. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.
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M.M. serves on the scientific advisory board and/or holds stock from Compugen, Myeloid Therapeutics, Asher Bio, Dren Bio, Oncoresponse, Owkin, OSE, DemBio, Larkspur, Innate Pharma and Genenta; and receives funding for contracted research from Regeneron and Boerhinger Ingelheim. The above interests are not directly relevant to this article. The other authors declare no competing interests.
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Glossary
- Bispecific antibodies
-
(BsAbs). Engineered antibodies that contain two binding sites directed at two different epitopes.
- CCR7-mediated migration
-
A main mode of migration for dendritic cells to the secondary lymphoid organs upon maturation in response to CCL19 and CCL22, ligands for CCR7.
- cGAS–STING pathway
-
A signalling pathway involving cyclic GMP–AMP synthase (cGAS) and stimulator of interferon genes (STING) that detects cytosolic DNA and activates the production of type I interferons in response to infection or cellular stress.
- Damage-associated molecular patterns
-
(DAMPs). Molecules released by dying cells that trigger immune responses.
- DC maturation
-
A process by which dendritic cells (DCs) gain the ability to interact with other haematopoietic cells (predominantly T cells) and shape the downstream immune response towards either a tolerogenic or immunogenic outcome.
- Exhausted T cell progenitors
-
A distinct subpopulation of T cells found in chronic infection and cancer that can self-renew, proliferate and differentiate into either terminally exhausted T cells or cytolytic effector T cell fates.
- Immunogenic responses
-
In dendritic cell-mediated immunity, immunogenic responses arise when a dendritic cell-presented antigen elicits T cell activation, proliferation and release of immunostimulatory cytokines.
- Indoleamine 2,3-dioxygenase 1
-
(IDO1). An enzyme that degrades tryptophan to kynurenines, which can promote activation and differentiation of regulatory T cells.
- Lipid nanoparticles
-
(LNPs). Nanoparticles composed of various mixtures of lipids optimized for nanoparticle stability, cell entry and endosomal escape; these entities are as a technical platform to deliver drugs and/or genetic material (for example, mRNA).
- Metabolic rewiring
-
Changes in the metabolic state of a cell, often brought on to adapt to environmental perturbations or to facilitate various functions of a cell upon differentiation or transition to another cell state.
- Ontogeny
-
The developmental lineage that gives rise to a specific cell type.
- Pathogen-associated molecular patterns
-
(PAMPs). Highly conserved, molecular motifs that derive from microorganisms and are recognized by pattern recognition receptors.
- Pattern recognition receptors
-
(PRRs). A diverse group of receptors expressed both on the cell surface and inside the cell that recognize pathogen-associated molecular patterns and damage-associated molecular patterns and initiate immune responses.
- Phagosomal acidification
-
The phagosome is a cellular compartment containing engulfed material and its acidification facilitates the degradation of internalized cargo by acidic hydrolases.
- SMAC mimetics
-
A class of small-molecule inhibitors that structurally resemble the amino-terminal inhibitor of apoptosis (IAP)-binding motif and can inhibit various IAP proteins.
- SOCS1 and SOCS3
-
Proteins that regulate cytokine signalling by inhibiting the JAK–STAT pathway.
- Tertiary lymphoid structures
-
(TLSs). Ectopic lymphoid structures found in inflammatory tissue sites that feature several organizational aspects akin to a lymph node including T cells, B cells, dendritic cells and high endothelial venules.
- Tolerogenic responses
-
In dendritic cell-mediated immunity, tolerogenic responses arise when a dendritic cell-presented antigen induces a T cell regulatory response.
- Transcriptional programme
-
A set of genes, of which changes in expression are highly correlated with one another; is differentially expressed by a distinct cluster of cells; and is linked with a putative function (or functions) of the cell cluster in question.
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Moon, C.Y., Belabed, M., Park, M.D. et al. Dendritic cell maturation in cancer. Nat Rev Cancer 25, 225–248 (2025). https://doi.org/10.1038/s41568-024-00787-3
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DOI: https://doi.org/10.1038/s41568-024-00787-3
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