Regulated cell death in cancer: from pathogenesis to treatment

Abstract

Regulated cell death (RCD), including apoptosis, pyroptosis, necroptosis, and ferroptosis, is regulated by a series of evolutionarily conserved pathways, and is required for development and tissue homeostasis. Based on previous genetic and biochemical explorations of cell death subroutines, the characteristics of each are generally considered distinctive. However, recent in-depth studies noted the presence of crosstalk between the different forms of RCD; hence, the concept of PANoptosis appeared. Cancer, a complex genetic disease, is characterized by stepwise deregulation of cell apoptosis and proliferation, with significant morbidity and mortality globally. At present, studies on the different RCD pathways, as well as the intricate relationships between different cell death subroutines, mainly focus on infectious diseases, and their roles in cancer remain unclear. As cancers are characterized by dysregulated cell death and inflammatory responses, most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells. In this review, we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression. The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised. We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds, immune checkpoint inhibitors, and nanoparticles. Together, these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.

Figure 1

Core molecular mechanism of regulated cell death for (A) apoptosis, (B) pyroptosis, and (C) necroptosis. Dotted lines indicate dual function. Bid: BH3-interacting domain death agonist; Cty C: Cytochrome c; DAI: DNA-dependent activator of IFN-regulatory factors; DAMP: Damage-related molecular patterns; DISC: Death-inducing signaling complex; GSDM: Gasdermin; IFN: Interferons; LPS: Lipopolysaccharide; MLKL: Mixed line age kinase domain-like pseudokinase; PAMP: Pathogen associated molecular pattern; RCD: Regulated cell death; RIPK: Receptor-interactive protein kinase; TICAM1: Toll like receptor adaptor molecule 1.

Figure 2

The regulation of PANoptotic cell death. PANoptosis pathway is considered to be activated by a cytoplasmic multimeric protein complex named the PANoptosome, such as AIM2-, ZBP1-, and RIPK-PANoptosome, that has key features of pyroptosis, apoptosis, and/or necroptosis, but one that cannot be accounted for by any of these three PCD pathways alone. AIM2: Absent in melanoma 2; CARD: Caspase activation and recruitment domain; DAMP: Damage-related molecular patterns; GSDM: Gasdermin; MLKL: mixed line age kinase domain-like pseudokinase; PAMP: Pathogen associated molecular pattern; RIPK: Receptor-interactive protein kinase.

Figure 3

Core molecular mechanism of ferroptosis and the potential molecules that modulate both ferroptosis and PANoptosis (apoptosis, necroptosis, and pyroptosis). Dotted lines indicate dual function. ROS: Reactive oxygen species.