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Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity

Nature Reviews Cancer volume 24, pages 299–315 (2024)Cite this article

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Abstract

Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis — a largely immunologically silent form of cell death — there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8+ T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks.

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Fig. 1: Extrinsic and intrinsic pathways to cell death.
Fig. 2: Necroptotic signalling.
Fig. 3: Apoptotic and necroptotic cells have differential effects on DC maturation and immune responses.

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Acknowledgements

P.M. is funded by Breast Cancer Now as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre (CTR-QR14-007) and by Cancer Research UK (CRUK; C26866/A24399). D.A. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) — Projektnummer 125440785 — SFB 877, Project B2. J.S. is funded by NHMRC Investigator Grant 1195038.

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Authors and Affiliations

  1. The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK

    Pascal Meier & Arnaud J. Legrand

  2. Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Dieter Adam

  3. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    John Silke

Authors
  1. Pascal Meier
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  2. Arnaud J. Legrand
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  3. Dieter Adam
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  4. John Silke
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Pascal Meier, Dieter Adam or John Silke.

Ethics declarations

Competing interests

J.S. contributes to a project developing necroptosis inhibitors in collaboration with Anaxis Pharma. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Junying Yuan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

SMARTapp: http://www.bioinfo-zs.com/smartapp

TCGA: https://www.cancer.gov/tcga

Glossary

Adjuvanticity

Refers to the property of a substance, called an adjuvant, that enhances the immune response to an antigen.

Anoikis

A cell death mechanism that occurs when cells detach from their surrounding extracellular matrix or lose contact with neighbouring cells.

Cancer epitopes

Short protein or peptide fragments derived from cancer-associated proteins that are recognized by the immune system as foreign or abnormal.

CD8+ T cell cross-priming

A process by which dendritic cells present antigens from extracellular pathogens or abnormal cells to CD8+ T cells, also known as cytotoxic T lymphocytes. In addition, immunogenic dendritic cells provide signal 2 and signal 3, which trigger the activation of cytotoxic T lymphocytes.

Cold tumours

A term used in the field of cancer immunology to describe tumours that have a limited immune response or a low presence of immune cells within the tumour microenvironment.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that are released by stressed, damaged or dying cells.

Death receptors

The receptors for TNF, FAS ligand and TRAIL that contain an intracellular protein–protein interaction domain, known as the death domain, and can mediate cell death.

Eat-me signals

Molecular cues or markers displayed on the surface of cells that are undergoing apoptosis or other forms of cell death.

Efferocytosis

The process by which dead or dying cells are recognized, engulfed and cleared by phagocytes.

Endogenous retroelements

Endogenous genetic elements capable of self-amplification, found within the genome of eukaryotic organisms, including retrotransposons and endogenous retroviruses; their DNA can be transcribed into RNA, converted back into identical DNA via reverse transcription, and then inserted into the genome at particular target sites.

Endosomal sorting complexes required for transport (ESCRT) machinery

A group of protein complexes that play a crucial role in various membrane remodelling and trafficking processes within eukaryotic cells.

Engulfment process

Also known as phagocytosis. A cellular mechanism by which specialized cells called phagocytes engulf and internalize particles, cells or other materials from their surroundings.

Entotic cell death

A form of cellular cannibalism in which one cell engulfs and kills another cell through microtubule-associated protein 1A/1B light chain 3-associated phagocytosis and the lysosomal degradation pathway.

Ferroptosis

A form of cell death characterized by the accumulation of lipid peroxides, particularly those containing polyunsaturated fatty acids, which leads to membrane damage and, ultimately, cell death.

Find-me signals

Soluble signals that are released by dying cells into the milieu to attract phagocytes and stimulate their scavenging potential.

Flotillins

A family of membrane-associated proteins that are involved in various cellular processes related to membrane organization, signalling and trafficking.

Immune-related adverse events

(irAEs). A set of side effects or complications that can arise as a result of the immune system being activated by immunotherapy treatments such as immune-checkpoint inhibitors, cancer vaccines and other immune-modulating therapies.

Immune tolerance

A state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response.

Inflammasome

A large supramolecular platform that mediates the activation of a caspase 1-dependent pro-inflammatory response characterized by the production of IL-1β and IL-18.

Mitochondrial outer membrane permeabilization

(MOMP). Refers to a crucial event in the process of the intrinsic cell death pathway of apoptosis, where the outer mitochondrial membrane becomes permeable, leading to the release of various pro-apoptotic factors from the mitochondria into the cytoplasm.

Mitochondrial permeability transition-driven necrosis

A form of necrotic cell death that is driven by mitochondrial dysfunction by the opening of the mitochondrial permeability transition pore and is triggered by increases in matrix levels of Ca2+ and reactive oxygen species.

Necrosome

An amyloid-like supramolecular platform that enables the physical and functional interaction of the proteins RIPK1, RIPK3 and MLKL, triggering necroptosis.

NETosis

A unique form of neutrophil cell death that is characterized by the release of decondensed chromatin to form neutrophil extracellular traps (NETs) that capture microbes but can also capture and activate platelets to trigger clotting.

Nucleic acid sensors

Intracellular pattern recognition receptors involved in the detection of cytosolic nucleic acids.

Oxeiptosis

A reactive oxygen species-induced cell death pathway that leads to caspase-independent, non-inflammatory cell death and involves the proteins KEAP1, PGAM5 and AIFM1.

Oxytosis

Also known as oxidative stress-induced cell death. A form of cell death that is triggered by excessive oxidative stress within a cell.

Parthanatos

A form of cell death that involves hyper-activation of poly(ADP-ribose) polymerase enzymes and the subsequent depletion of cellular NAD+ and ATP.

Pattern recognition receptors

(PRRs). Innate immune receptors capable of recognizing pathogen-associated molecular patterns or host-derived DAMPs.

Persister cells

Subpopulations of cells that resist treatment by changing to a state of dormancy or quiescence and which can reactivate and multiply when treatment has stopped.

Short interspersed nuclear elements

Non-autonomous, non-coding transposable DNA elements of about 100–700 base pairs in length that amplify themselves throughout eukaryotic genomes, often through RNA intermediates.

SMAC mimetics

A class of small pharmacological molecules that mimic the amino-terminal inhibitor of apoptosis (IAP)-binding motif and selectively bind to the baculoviral IAP repeat 2 (BIR2) and BIR3 domains of numerous IAPs.

Suppressive myeloid cells

A heterogeneous group of immune cells from the myeloid lineage with immunosuppressive activities.

Therapeutic index

The ratio of the dose of a drug that exerts toxicity in 50% of the population to the dose that exerts a therapeutic or effective response in 50% of the population.

Tumour lysis syndrome

A potentially life-threatening medical condition that can occur as a result of rapid and massive cell breakdown in response to cancer treatment.

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Meier, P., Legrand, A.J., Adam, D. et al. Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nat Rev Cancer 24, 299–315 (2024). https://doi.org/10.1038/s41568-024-00674-x

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