Matrix stiffening-driven hepatocellular carcinoma progression through OASL-mediated cGAS-STING repression and...

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is characterized by matrix stiffening, which disrupts the tumor microenvironment (TME) and impairs anti-tumor immunity.
• The role of interferon-stimulated gene 2'-5'-oligoadenylate synthetase-like (OASL) in stiffness-driven HCC progression is not well understood.

Purpose of the Study:

• To investigate the role of OASL in hepatocellular carcinoma (HCC) progression within the context of tumor microenvironment (TME) stiffness.
• To explore the molecular mechanisms by which OASL influences matrix stiffness, cancer cell behavior, and anti-tumor immunity in HCC.

Main Methods:

• Constructed polyacrylamide gels to mimic soft and stiff TME conditions.
• Utilized transcriptome sequencing to identify OASL as a stiffness-associated gene.
• Performed in vitro and in vivo assays, including cell behavior assessments, molecular interaction studies (Co-IP, Western blot), and analysis of the cGAS-STING pathway and macrophage polarization in a mouse model.

Main Results:

• OASL was upregulated in HCC cells on stiff substrates, correlating with poor prognosis.
• OASL knockdown reduced matrix stiffness, suppressed HCC cell proliferation and migration, and promoted apoptosis.
• OASL inhibited the cGAS-STING pathway, enhanced M1 macrophage polarization, and its silencing in vivo attenuated tumor growth and boosted anti-tumor immunity.

Conclusions:

• OASL promotes HCC progression by sustaining high matrix stiffness and suppressing anti-tumor immunity via the cGAS-STING pathway.
• Targeting OASL presents a potential therapeutic strategy to remodel TME stiffness and restore anti-tumor immunity in HCC.