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Gasdermin-Mediated Pyroptosis: Novel Strategies Against Colorectal Cancer
Kaibo Guo1,2, Yuqian Feng3, Jiamin Lu4
1Department of Oncology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
Abstract:
Pyroptosis, a form of programmed cell death mediated by gasdermin proteins, has gained attention for its dual role in colorectal cancer (CRC) progression and therapy. While chronic pyroptosis-driven inflammation can promote tumorigenesis, acute induction of pyroptosis in tumor cells offers promising antitumor effects. Understanding the mechanisms and implications of pyroptosis in CRC could lead to novel therapeutic strategies. Gasdermin proteins, particularly GSDMD and GSDME, are central to pyroptotic processes in CRC. GSDMD activation, often through NLRP3 inflammasome signaling or chemotherapeutic agents like simvastatin, induces pyroptosis and modulates immune infiltration. Conversely, GSDMC has been implicated in CRC progression under metabolic stress by recruiting immunosuppressive cells. Although frequently silenced in CRC, GSDME enhances sensitivity to chemoradiation and synergizes with immune checkpoint inhibitors by releasing immunostimulatory molecules. Inflammasomes, notably NLRP3 and AIM2, also play significant roles in CRC pathogenesis through pyroptosis and cytokine secretion. NLRP3 activation exacerbates tumor growth via inflammatory pathways, while AIM2 exerts tumor-suppressive effects, especially in BRAF-mutant CRC. The gut microbiota further influences inflammasome activity, with certain strains promoting chemoresistance and others enhancing antitumor immunity. Therapeutically, inducing pyroptosis synergizes with conventional therapies and immunotherapies, overcoming apoptosis resistance and resensitizing tumors. Pyroptosis releases tumor antigens and damage-associated molecular patterns, recruiting cytotoxic lymphocytes and natural killer cells, thereby remodeling the immunosuppressive microenvironment. Pyroptosis represents a double-edged sword in CRC, offering both challenges and opportunities. Harnessing its antitumor potential while mitigating pro-tumorigenic inflammation requires innovative strategies. Future research should focus on elucidating the isoform-specific roles of gasdermins, optimizing therapeutic approaches to induce pyroptosis.
Insights
Pyroptosis, a programmed cell death, has a dual role in colorectal cancer (CRC). While inflammation can promote tumors, inducing pyroptosis offers antitumor effects and enhances cancer therapies.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Pyroptosis, a programmed cell death pathway, is mediated by gasdermin proteins and plays a complex role in colorectal cancer (CRC).
- Chronic inflammation driven by pyroptosis can promote CRC tumorigenesis.
- Acute pyroptosis induction in tumor cells shows potential for antitumor effects.
Purpose of the Study:
- To elucidate the multifaceted roles of pyroptosis and its mediators, gasdermin proteins and inflammasomes, in colorectal cancer.
- To explore the therapeutic implications of targeting pyroptosis in CRC treatment.
- To understand the interplay between pyroptosis, the tumor microenvironment, and gut microbiota in CRC.
Main Methods:
- Analysis of gasdermin protein functions (GSDMD, GSDME, GSDMC) in CRC progression and therapy.
- Investigation of inflammasome pathways (NLRP3, AIM2) and their impact on CRC pathogenesis.
- Examination of the influence of gut microbiota on pyroptosis and CRC outcomes.
- Review of therapeutic strategies involving pyroptosis induction in combination with conventional and immunotherapies.
Main Results:
- Gasdermin proteins exhibit isoform-specific roles; GSDMD activation can induce pyroptosis and modulate immune infiltration, while GSDMC may promote CRC progression.
- GSDME expression enhances sensitivity to chemoradiation and synergizes with immune checkpoint inhibitors.
- NLRP3 inflammasome activation can exacerbate CRC growth, whereas AIM2 shows tumor-suppressive effects, particularly in BRAF-mutant CRC.
- Gut microbiota composition affects chemoresistance and antitumor immunity.
- Pyroptosis induction synergizes with existing therapies, overcoming apoptosis resistance and remodeling the tumor microenvironment by releasing tumor antigens and DAMPs.
Conclusions:
- Pyroptosis presents a double-edged sword in colorectal cancer, with potential for both promoting and combating the disease.
- Targeting pyroptosis, particularly through GSDME, offers promising therapeutic avenues for CRC, enhancing responses to conventional treatments and immunotherapies.
- Future research should focus on isoform-specific gasdermin functions and optimizing pyroptosis-inducing therapeutic strategies for CRC.
