Pyroptosis Mechanisms in Cancer Immunology and Immunotherapy

Pyroptosis is a form of lytic, inflammatory programmed cell death that has emerged as a key regulator in cancer immunology and immunotherapy. Triggered by the activation of inflammasomes and execution by members of the gasdermin family, pyroptotic cells release pro-inflammatory cytokines and antigenic cellular contents that reshape the tumour microenvironment and recruit innate and adaptive immune effectors. This modality differs from apoptosis in its membrane-rupturing morphology and capacity to promote robust antitumour immunity. Mechanistically, canonical pyroptosis involves caspase-1-mediated cleavage of gasdermin D, whereas non-canonical pathways utilise caspases-4/5/11, caspase-3/8, or granzyme B to activate gasdermin E. These pathways converge on membrane pore formation, cell swelling and release of damage-associated molecular patterns. In the context of cancer, induced pyroptosis can sensitize tumours to immune checkpoint blockade by enhancing neoantigen presentation and T-cell infiltration, yet uncontrolled pyroptosis in normal tissues may underlie therapy-related toxicities. Recent advances have elucidated molecular switches between apoptosis and pyroptosis, revealed mitochondrial permeabilisation by gasdermin N-terminal fragments as a feed-forward amplifier of death signalling, and demonstrated engineered nanotherapeutics that couple pyroptotic induction with photodynamic or sonodynamic therapy. Together, these insights offer avenues to harness pyroptosis as a double-edged tool for cancer eradication and immune modulation.

Research from Nature Portfolio

Recent studies have delineated the central role of gasdermin family members in linking apoptotic and pyroptotic programmes. One investigation revealed that caspase-3 cleavage of DFNA5 (gasdermin E) during apoptosis generates an N-terminal fragment that permeabilises the plasma membrane, driving secondary necrosis with inflammatory features characteristic of pyroptosis. This work established DFNA5 as a molecular switch between silent apoptosis and immunogenic pyroptosis. Complementary findings showed that gasdermin N-terminal pores not only disrupt the plasma membrane but also target mitochondrial membranes, releasing cytochrome c to amplify caspase-3 activation and reinforce cell death signals. These studies highlight a bidirectional crosstalk between mitochondrial apoptosis and pyroptosis, positioning gasdermins as integrative hubs for therapeutic manipulation of cell death modalities in cancer.

Pyroptosis Mechanisms in Cancer Immunology and Immunotherapy publication trend

The graph below shows the total number of articles in pyroptosis mechanisms in cancer immunology and immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Pyroptosis: A lytic form of programmed cell death executed by gasdermin pore formation, leading to membrane rupture and inflammation.

Inflammasome: A multiprotein complex that activates inflammatory caspases in response to cellular stress or pathogen signals.

Gasdermins: A family of pore-forming proteins cleaved by caspases or granzymes to initiate pyroptosis.

Damage-Associated Molecular Patterns (DAMPs): Endogenous molecules released by dying cells that stimulate immune responses.

Caspases: A group of cysteine proteases that regulate apoptotic and inflammatory cell death pathways.

References

1. Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. Signal Transduction and Targeted Therapy (2024).
2. Oxygen‐carrying semiconducting polymer nanoprodrugs induce sono‐pyroptosis for deep‐tissue tumor treatment. Exploration (2024).
3. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nature Communications (2017).
4. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nature Communications (2019).
5. Pyroptosis: a new paradigm of cell death for fighting against cancer. Journal of Experimental & Clinical Cancer Research (2021).
6. Microenvironment‐Responsive Prodrug‐Induced Pyroptosis Boosts Cancer Immunotherapy. Advanced Science (2021).