Regulated Cell Death Mechanisms in Cancer

Regulated cell death (RCD) encompasses genetically controlled pathways that eliminate damaged or unwanted cells and maintain tissue integrity. In cancer, evasion of RCD underlies unchecked proliferation, metastasis and resistance to therapy. Classical apoptosis involves caspase activation, DNA fragmentation and membrane blebbing but is often suppressed in tumours through p53 mutations, overexpression of BCL-2 family proteins and altered death receptor signalling. Alternative RCD modalities—necroptosis, pyroptosis and ferroptosis—are defined by distinct molecular triggers: receptor-interacting protein kinases and MLKL in necroptosis; inflammasome-activated gasdermins in pyroptosis; and iron-catalysed lipid peroxidation in ferroptosis. Recent discoveries have expanded the repertoire to include cuproptosis, driven by copper binding to lipidated tricarboxylic acid cycle proteins, and alkaliptosis, a pH-dependent death regulated by NF-κB-CA9 or ATP6V0D1-STAT3 axes. Crosstalk among these pathways influences the immunogenicity of the tumour microenvironment, shaping responses to chemotherapy, radiotherapy and immunotherapy. Emerging therapeutic strategies aim to exploit specific RCD vulnerabilities with small-molecule inducers or inhibitors, offering prospects for precision cancer treatment with reduced collateral damage.

Research from Nature Portfolio

Recent studies have elucidated the metabolic and epigenetic control of alkaliptosis in pancreatic ductal adenocarcinoma. Acetyl-CoA short-chain synthase family member 2 (ACSS2) upregulation enhances intracellular acetyl-CoA supply, promoting histone acetylation and NF-κB-dependent downregulation of carbonic anhydrase 9, thereby sensitising cells to an alkaliptosis activator. Genetic suppression of ACSS2 preserves intracellular pH and impedes cell death, while pharmacological inhibition of histone deacetylases reinstates alkaliptosis sensitivity. These findings reveal a metabolic-epigenetic axis governing pH-driven tumour cell death and highlight ACSS2 as a potential therapeutic target in apoptosis-resistant cancers.

Regulated Cell Death Mechanisms in Cancer publication trend

The graph below shows the total number of articles in regulated cell death mechanisms in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Regulated cell death (RCD): genetically controlled processes leading to organised cell demise in response to intrinsic or extrinsic signals.

Apoptosis: caspase-mediated RCD characterised by DNA fragmentation and cell shrinkage without provoking inflammation.

Necroptosis: regulated necrotic death executed by RIPK1/RIPK3 kinases and MLKL, culminating in plasma membrane rupture.

Pyroptosis: inflammatory RCD driven by inflammasome activation and gasdermin-mediated pore formation, releasing cytokines.

Ferroptosis: iron-dependent lipid peroxidation causing oxidative membrane damage and cell death.

Cuproptosis: copper-induced RCD via direct binding to lipidated tricarboxylic acid cycle proteins, disrupting mitochondrial function.

Alkaliptosis: pH-dependent cell death triggered by intracellular alkalinisation and regulated by NF-κB- or ATP6V0D1-STAT3-mediated pathways.

Tumour microenvironment (TME): the cellular and molecular milieu surrounding cancer cells, influencing growth, immune evasion and therapy response.

References

1. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. Journal of Hematology & Oncology (2022).
2. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduction and Targeted Therapy (2022).
3. ATP6V0D1 promotes alkaliptosis by blocking STAT3-mediated lysosomal pH homeostasis. Cell Reports (2022).
4. Mechanisms of alkaliptosis. Frontiers in Cell and Developmental Biology (2023).
5. ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells. Scientific Reports (2023).
6. Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy. Frontiers in Immunology (2022).