Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity.
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Research in the K.E.d.V. laboratory is funded by the Netherlands Organization for Scientific Research (grant NWO-VICI 91819616), the Dutch Cancer Society (KWF10623, KWF13191 and KWF14339) and the Oncode Institute. The authors thank K. Kos, D. Duits, H. Garner and C. Burrello for their insightful input and all members of the K.E.d.V. laboratory for valuable discussions.
K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics. A.v.W. declares no competing interests.
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An intracellular recycling process that selectively degrades damaged proteins, lipids, nucleic acids, metabolites and organelles to maintain cell homeostasis and viability.
- Cancer immune landscape
The composition, location, phenotype and functional state of immune cells in tumours.
- Cancer immunotherapy
Therapeutic interventions that activate or suppress aspects of the immune system, including immune checkpoint blockade, to treat cancer.
- Cytotoxic T lymphocytes
(CTLs). A group of antigen-specific T cells that have the capacity to directly target and destroy cells that express the cognate antigen on their surface, presented by major histocompatibility complex molecules.
Small endosomal-derived lipid bilayer membrane vesicles that carry cargo to target cells they encounter, which results in reprograming of recipient cells distal from their release.
- Extracellular vesicles
Small lipid-enclosed vesicles, including microvesicles, exosomes and apoptotic bodies, that carry cellular cargo such as DNA, RNA, protein or lipids that can be taken up by other cells, where the release of the extracellular vesicle cargo can modulate cell function.
- Immune checkpoint molecules
Co-stimulatory or co-inhibitory receptors and their ligands that exert stimulatory or inhibitory effects, respectively, on immune responses and that function as ‘gatekeepers’ by balancing immune cell activation and inhibition.
- Immune escape
A variety of strategies that are exploited by cancer cells to avoid discovery and destruction by the immune system.
Short sequences of DNA (one to ten nucleotides) that are tandemly repeated in the genome.
- Myeloid-derived suppressor cells
(MDSCs). A heterogeneous population of myeloid cells, consisting of (immature) monocytic and neutrophilic cells with immunosuppressive capacities.
A state of functional activation of a myeloid immune cell in response to specific environmental and tumour-derived signals to induce, for example, the immunostimulatory M1-like or immunosuppressive M2-like polarization of macrophages.
- Tumour microenvironment
(TME). The environment around the tumour, that besides cancer cells is composed of a large diversity of host cells, including immune cells, fibroblasts and endothelial cells, as well as extracellular matrix components, blood vessels and signalling molecules, such as chemokines, cytokines and growth factors.
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van Weverwijk, A., de Visser, K.E. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer 23, 193–215 (2023). https://doi.org/10.1038/s41568-022-00544-4