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Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives
Chen Huang1, Jiayi Li2, Ruiyan Wu3
1Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Abstract:
Pyroptosis is a distinct form of programmed cell death characterized by the rupture of the cell membrane and robust inflammatory responses. Increasing evidence suggests that pyroptosis significantly affects the tumor microenvironment and antitumor immunity by releasing damage-associated molecular patterns (DAMPs) and pro-inflammatory mediators, thereby establishing it as a pivotal target in cancer immunotherapy. This review thoroughly explores the molecular mechanisms underlying pyroptosis, with a particular focus on inflammasome activation and the gasdermin family of proteins (GSDMs). It examines the role of pyroptotic cell death in reshaping the tumor immune microenvironment (TIME) involving both tumor and immune cells, and discusses recent advancements in targeting pyroptotic pathways through therapeutic strategies such as small molecule modulators, engineered nanocarriers, and combinatory treatments with immune checkpoint inhibitors. We also review recent advances and future directions in targeting pyroptosis to enhance tumor immunotherapy with immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines. This study suggested that targeting pyroptosis offers a promising avenue to amplify antitumor immune responses and surmount resistance to existing immunotherapies, potentially leading to more efficacious cancer treatments.
Insights
Pyroptosis, a programmed cell death, enhances antitumor immunity by releasing inflammatory signals. Targeting pyroptosis pathways offers a promising strategy to improve cancer immunotherapy and overcome treatment resistance.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Pyroptosis is a key programmed cell death pathway influencing the tumor microenvironment.
- It releases damage-associated molecular patterns (DAMPs) and inflammatory mediators, impacting antitumor immunity.
- Pyroptosis is recognized as a critical target for cancer immunotherapy.
Purpose of the Study:
- To review the molecular mechanisms of pyroptosis, focusing on inflammasome activation and gasdermin proteins.
- To examine pyroptosis's role in reshaping the tumor immune microenvironment (TIME).
- To discuss therapeutic strategies targeting pyroptosis for enhanced cancer immunotherapy.
Main Methods:
- Literature review of pyroptosis mechanisms, TIME modulation, and therapeutic interventions.
- Analysis of inflammasome activation and gasdermin family protein functions.
- Exploration of small molecule modulators, nanocarriers, and combination therapies.
Main Results:
- Pyroptosis significantly impacts the TIME by releasing DAMPs and pro-inflammatory cytokines.
- Targeting pyroptosis pathways can enhance immune cell activity against tumors.
- Emerging therapies include small molecules, nanocarriers, and combinations with immune checkpoint inhibitors.
Conclusions:
- Targeting pyroptosis is a promising strategy to boost antitumor immune responses.
- This approach may help overcome resistance to current cancer immunotherapies.
- Further research into pyroptosis modulation could lead to more effective cancer treatments.
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