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

Matrix stiffening is a hallmark of hepatocellular carcinoma (HCC), disrupting the tumor microenvironment (TME) and impairing anti-tumor immunity. Although the interferon-stimulated gene 2'-5'-oligoadenylate synthetase-like (OASL) is dysregulated in cancers, its role in stiffness-driven HCC progression remains unclear.

We constructed polyacrylamide gels (5 kPa soft, 16 kPa stiff) to mimic the mechanical TME. Transcriptome sequencing identified OASL as a stiffness-associated gene. We subsequently performed in vitro assays (CCK-8, Transwell, apoptosis) to assess HCC cell behaviors. Furthermore, Co-IP, ELISA, Western blot, and immunofluorescence were utilized to explore molecular interactions. For in vivo validation, we established a subcutaneous HCC model in C57BL/6 mice and then employed immunohistochemistry and flow cytometry to evaluate OASL's effects on matrix stiffness, the cGAS-STING pathway, and macrophage polarization.

OASL was up-regulated in HCC cells on stiff substrates, correlating with elevated stiffness markers (COL1A2, YAP, α-SMA) and poor prognosis. OASL knockdown reduced matrix stiffness, suppressed proliferation and migration, and promoted apoptosis. It activated the cGAS-STING pathway via direct interaction with cGAS and inhibition of cGAMP generation, enhancing M1 macrophage polarization. However, the STING inhibitor C-176 reversed all these effects. In vivo, OASL silencing attenuated tumor growth, down-regulated stiffness-related proteins, and boosted anti-tumor immunity.

OASL promotes HCC progression by inhibiting the cGAS-STING pathway, sustaining high matrix stiffness, and suppressing M1 macrophage polarization. Targeting OASL may offer a novel therapeutic strategy to remodel TME stiffness and restore anti-tumor immunity in HCC.