Dual function of Gasdermin E: pyroptosis-mediated pan-cancer suppression versus HCC-specific oncogenic activity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Gasdermin E (GSDME) is a key pyroptosis executor with a dual role in tumorigenesis, acting as both a tumor suppressor and promoter.
• GSDME is epigenetically silenced via promoter hypermethylation in various solid tumors, including gastric, colorectal, and breast cancers.
• GSDME activation releases inflammatory cytokines (IL-1β, IL-18), enhances CD8+ T cell infiltration, and improves chemosensitivity, conferring tumor-suppressive effects.

Purpose of the Study:

• To investigate the aberrant GSDME overexpression in hepatocellular carcinoma (HCC).
• To elucidate the pyroptosis-independent pro-tumor pathways driven by GSDME in HCC.
• To explore precision strategies for controlling GSDME's functional switch in cancer therapy.

Main Methods:

• Analysis of GSDME expression patterns in HCC.
• Investigation of GSDME's role in immune suppression and anti-PD-1 therapy resistance in HCC.
• Exploration of GSDME-mediated pyroptosis activation in HCC.

Main Results:

• HCC exhibits aberrant GSDME overexpression, contributing to immune suppression and resistance to anti-PD-1 therapy via pyroptosis-independent mechanisms.
• GSDME's function is context-dependent, showing plasticity in response to microenvironmental signals.
• Specific interventions can activate GSDME-mediated pyroptosis in HCC.

Conclusions:

• Understanding GSDME's dual role and overexpression mechanisms in HCC is crucial.
• Targeting pyroptosis-independent pro-tumor pathways and controlling GSDME's functional switch are key therapeutic challenges.
• Future research integrating advanced multi-omics and spatial transcriptomics can establish "pyroptosis immunomodulation" for multidimensional "microenvironment reprogramming" in cancer treatment.