Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy with limited therapeutic options.
• Tissue factor (TF) is highly expressed in PDAC and is a potential therapeutic target.
• The functional role of TF in PDAC and its interaction with innate immune pathways remain unclear.

Purpose of the Study:

• To investigate the relationship between TF expression and the STING pathway in PDAC.
• To elucidate the mechanisms by which TF influences the STING pathway.
• To evaluate the therapeutic potential of TF inhibition in PDAC.

Main Methods:

• Analysis of patient data correlating TF expression with survival and immune markers.
• Experimental models of PDAC (mouse and human) to study TF's role in STING activation.
• Inhibition of TF using genetic (TF-KO/shRNA) and antibody-based approaches (anti-TF antibody HuSC1-39).
• Assessment of STING pathway activation, immune cell infiltration, and anti-tumor efficacy in vitro and in vivo.

Main Results:

• TF overexpression in PDAC patients correlated with poor survival, reduced STING pathway activation (P-STING/P-TBK1), lower interferon-stimulated genes (ISGs), chemokines, and cytotoxic immune cells.
• Tumor cell-intrinsic TF expression suppressed cytosolic DNA sensing and cGAS-STING activation via TREX1-dependent clearance of micronuclear DNA.
• TF inhibition (TF-KO/shRNA or anti-TF antibody) led to TREX1 degradation, restored STING/TBK1 phosphorylation, and promoted STING/IRF3-dependent IFN and chemokine production.
• TF inhibition enhanced immune cell infiltration and anti-tumor efficacy, synergized with a STING agonist, and improved ADC efficacy in vitro and in vivo.

Conclusions:

• TF-targeted therapy can reprogram the tumor microenvironment from "immune desert" to "immune hot".
• TF inhibition effectively restores STING pathway activation and enhances anti-tumor immunity.
• TF-targeted therapy, alone or in combination with immunotherapy or STING agonists, shows promise for treating TF-positive PDAC and triple-negative breast cancer (TNBC).