Immunogenic cell death in cancer therapy: Present and emerging inducers

Abstract

In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long-lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.

Keywords: ICD inducers; antitumour effects; damage-associated molecular patterns; dendritic cells; immune system; immunogenic cancer cell death.

Figure 1

Schematic representation of the induction of immunogenic cell death (ICD). After treatment with different ICD inducers, cancer cells are induced to undergo apoptosis, which leads to cell swelling and bursting. Subsequently, the dying cells express damage‐associated molecular pattern (DAMPs) hallmarks, including the translocation of CRT from the endoplasmic reticulum to the cell surface, the release of high mobility group B1 from the nucleus, the extracellular secretion of adenosine triphosphate and the expression of HSPs on the cell surface

Figure 2

A schematic explaining the mechanism by which immunogenic cell death (ICD) is induced in dendritic cells and the effects of this progress on host immunity. After the induction of ICD, chronic exposure of damage‐associated molecular patterns (DAMPs) on cancer cells attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype. CRT/ERp57 provides an ‘eat me’ signal that promotes phagocytosis of the cell by DCs; similarly, extracellularly secreted adenosine triphosphate is regarded as a ‘find me’ signal, which triggers P₂X₇ receptors on DCs and is responsible for the activation of the NALP3‐ASC‐inflammasome and the secretion of IL‐1β. The binding of high mobility group B1 to Toll‐like receptor 4 (TLR4) and the expression of HSP70/90 have immunostimulatory properties that promote the processing of phagocytic cargo in DCs and accelerate the engulfment of antigenic components by DCs, which consequently stimulate specific T cell responses and the killing of more cancer cells

Figure 3

The induction pathway of immunogenic cell death (ICD). In the figure, there are three main pathways of ICD induction. Most ICD inducers are endoplasmic reticulum (ER) stress dependent, inducing the expression of damage‐associated molecular patterns (DAMPs) and triggering classic immunogenic cell death. Mitochondrial outer membrane permeabilization (MOMP) is another factor that stimulates NF‐κB activity and subsequently induces caspase‐independent cell death (CICD), which is also regarded as ICD