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The authors of some of our most popular Reviews look back on a decade of immunology.

In this Viewpoint, Nature Reviews Immunology invites eight experts in the field to share their thoughts on the key questions and challenges in MDSC research.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Gabrilovich and colleagues show that monocytic myeloid-derived suppressor cells (MDSCs) differentiate into polymorphonuclear MDSCs in individuals with tumors, demonstrating a demonstrating a distinct regulation of myeloid cell development in cancer.

Gabrilovich and colleagues discuss how the functional diversity of neutrophils in cancer can be ascribed to two functional states: classically activated neutrophils and pathologically activated myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expands during cancer, inflammation and infection. Here, the authors discuss the mechanisms of MDSC expansion and suppression of T-cell functionin vivo, and describe how these cells might be targeted for therapeutic purposes.

The role of type I interferon signalling in the control of myeloid derived suppressor cells (MDSC) activity remains controversial. Here the authors show that downregulation of type I interferon receptor is observed in MDSC from cancer patients and tumor-bearing mice and is required for the activation of their immune suppressive properties.

Neutrophils are linked to tumor progression. Gabrilovich and colleagues demonstrate that neutrophils have tumor-stage-dependent alterations in motility, function and metabolism: in early phases, they are highly motile with altered metabolism, whereas at later stages, they become highly suppressive.

Pathologically activated neutrophils, termed myeloid-derived suppressor cells, in the tumour microenvironment spontaneously undergo ferroptosis, which negatively regulates anti-tumour immunity through the release of oxygenated lipids, therefore limiting the activity of human and mouse T cells.

This Review from Gabrilovich and colleagues discusses our current understanding of the development and functions of myeloid-derived suppressor cells (MDSCs). Recent work has identified unique metabolic properties and gene expression patterns in MDSCs that could help in the development of new therapies for cancer and autoimmunity.

Dendritic cells in individuals with cancer and in mouse tumor models show an increase in triacylglycerides that seems to impair their antigen-processing capability and could thus contribute to tumor immune tolerance. This aberrant lipid load results from tumor-induced elevation of the scavenger receptor Msr1 on dendritic cells, and it can be targeted therapeutically to improve the efficiency of anticancer vaccines.

Gui et al. report that tumor-cell-derived factors induce p38a activation in lung fibroblasts, leading to inactivation of type I interferon signaling, matrix remodeling and neutrophil infiltration, thereby generating a metastasis-permissive niche.

Immune checkpoint therapies (ICT) are promising for treating various cancers, but response rates vary. Here the authors show, in mouse models, that tumor-infiltrating mast cells colocalize with regulatory T cells, coincide with local reduction of MHC-I and CD8 T cells, and is associated with resistance to ICT, which can be reversed by c-kit inhibitor treatment.

Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.

Gene signatures that predict response to immune checkpoint blockade (ICB) therapies in melanoma have been based on preclinical models and pre-treatment samples. Here the authors develop pathway-based signatures to predict ICB response in melanoma using on-treatment samples, leading to improved performance.

The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E₂.

Myeloid-derived suppressor cells (MDSCs) remain steeped in mystery and controversy — how do we identify them? How are they recruited to the tumour microenvironment? How do they suppress antitumour immunity? This Timeline article discusses the discovery of MDSCs and what we know now — and need to know in the future — about the role of MDSCs in cancer biology.

Myeloid-derived suppressor cells are induced in newborn mice by breast-milk-derived lactoferrin and confer protection in a model of necrotizing enterocolitis. Their frequency and suppressive activity is decreased in very low-weight infants.

Susceptibility to ferroptosis can be modulated by nitric oxide (NO^•) and NO synthase iNOS and through enrichment of activated M1 macrophages. NO inhibits the lipoxygenase 15-LOX that drives production of pro-ferroptotic lipids in macrophages.

Mitochondria have a controversial role in cancer. Here, the authors demonstrate the reprogramming of a neuronal network of mitochondrial trafficking in tumor cells, and identify Syntaphilin as a key protein that suppresses organelle dynamics thereby blocking chemotaxis and metastasis in mice.

Tumor-associated dendritic cells are defective in their ability to cross-present antigens, and they accumulate lipid bodies. Here the authors show that this defect is due to an impaired trafficking of peptide-MHC class I caused by the interaction of electrophilic lipids with chaperone heat shock protein 70.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population expanded in cancer and other chronic inflammatory conditions. Here the authors identify the challenges and propose a set of minimal reporting guidelines for mouse and human MDSC.

In this Review, Dai, Stockwell, Kroemer, Tang and colleagues offer a comprehensive discussion of the molecular regulation of ferroptosis and highlight how this may be potentially leveraged for therapeutic benefit for disease treatment.

Myeloid cells in the tumour microenvironment strongly influence tumour progression, and targeting these cells has been a key clinical focus. In this Review, Barry et al. discuss preclinical and clinical data on myeloid-targeting therapies, with a focus on how understanding context-specific effects might aid the design of successful clinical trials for these drugs.

The tumor immune microenvironment influences tumor progression and response to immunotherapy; its further characterization will improve therapeutic outcome.