Table 1 Comparison of different forms of cell death
From: Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives
| Â | Apoptosis | Ferroptosis | Pyroptosis | Necroptosis | Autophagy |
|---|---|---|---|---|---|
Type | PCD | PCD | PCD | PCD | PCD |
Causes | Death receptor pathway initiated by death ligand binding, ER pathway triggered by ER stress, mitochondrial pathway induced by DNA damage | Iron overload, lipid peroxidation, GPX4 inhibition, depletion of glutathione | Inflammasome stimulation, pathogen recognition, intracellular LPS sensing, activation of caspase-3/GSDME | death receptor activation when apoptosis is inhibited, pathogen recognition, caspase-8 inhibition, interferon signaling | Nutrient deprivation, metabolic stress, Gene regulation to use lysosomes to degrade damaged organelles and macromolecular substances |
Morphology | Cell shrinkage, chromatin condensation, nuclear fragmentation, membrane blebbing, formation of apoptotic bodies | Mitochondrial shrinkage, increased membrane density, loss of mitochondrial cristae, normal nuclear size | Cell swelling and expansion, pore formation, vesicular protrusions (pyroptosomes), nuclear condensation. DNA fragmentation | Cytoplasmic organelles swelling, cytoplasmic and nuclear disintegration | Autophagosomes with bilayer membranes, inflated organelles, pyknotic nuclei |
Cell Membrane | Integrity | Rupture | Rupture | Rupture | Integrity |
Characteristics | Highly regulated, energy dependent, PS externalization, DNA fragmentation at internucleosomal sites, non-inflammatory under physiological conditions | Iron accumulation, lipid peroxidation, oxidative stress-dependent, redox imbalance | IL-1β and IL-18 release, inflammasome activation, rapid cell lysis, release of pro-inflammatory cytokines | RIPK1 / RIPK3 /MLKL complex formation, backup mechanism to apoptosis under caspase-8 inhibition | Highly regulated, autophagosome engulfs damaged organelles or proteins, increased lysosomal activity, LC3 lipidation, context-dependent immunomodulation |
Molecular mechanism | Activation of initiator and executioner caspases, mitochondrial cytochrome c release, Bcl-2 family protein regulation | Inhibition of GPX4, depletion of glutathione, Fenton reaction producing ROS, accumulation of lipid peroxides, iron-catalyzed oxidative damage | Caspase-dependent, GSDMs cleavage, N-terminal fragment oligomerization | RIPK1 activation, RIPK3 and MLKL phosphorylation, MLKL-mediated membrane permeabilization | mTOR inhibition, ULK1 complex activation, Beclin-1/PI3K complex formation, autophagosome-lysosome fusion |
Effects on immunity | Typical immunologically silent, CRT exposure, ATP and HMGB1 release during immunogenic apoptosis, tolerogenic when cleared efficiently | Modulation of TIME, reduces MDSCs, polarizes TAMs, not universally immunogenic | Highly inflammatory and immunogenic, releases IL-1β and IL-18, activation of innate and adaptive immunity | Release of DAMPs, long genomic DNA and IL-6, low levels of ecto-CRT, effective for CD8+ T cell cross-priming | Extracellular release of DAMPs, PS exposure, context-dependent immunomodulatory effects, regulates inflammation |