PROTAC-based synthetic lethality strategy endogenously activates systemic STING to boost antitumor immunity

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The stimulator of interferon genes (STING) pathway is crucial for antitumor immunity, activated by cytosolic DNA.
• DNA repair mechanisms limit STING activation by preventing cytosolic DNA accumulation.
• Targeting DNA repair pathways offers a potential strategy to enhance STING-mediated immunity.

Purpose of the Study:

• To develop a novel therapeutic strategy using proteolysis-targeting chimeras (PROTACs) to degrade PARP1 and BRD4.
• To disrupt DNA repair machinery and induce nuclear-to-cytosolic DNA leakage for enhanced STING activation.
• To evaluate the antitumor efficacy and immune response elicited by this strategy.

Main Methods:

• Utilized PROTACs to mediate the degradation of PARP1 and BRD4.
• Induced synthetic lethality by disrupting DNA repair pathways.
• Assessed STING pathway activation, immune cell infiltration (CD8+ T cells, NK cells), and tumor growth in preclinical models.
• Evaluated the impact on pulmonary metastasis.

Main Results:

• PROTAC-mediated degradation of PARP1 and BRD4 successfully disrupted DNA repair.
• The strategy induced significant nuclear-to-cytosolic DNA leakage, surpassing the STING activation threshold.
• Demonstrated superior antitumor efficacy across multiple tumor models.
• Elicited robust CD8+ T cell- and NK cell-mediated antitumor immunity.
• Showed suppression of pulmonary metastasis progression.

Conclusions:

• The integration of synthetic lethality with PROTAC-mediated degradation of PARP1 and BRD4 is a viable strategy to enhance cGAS-STING-mediated innate immunity.
• This approach overcomes limitations imposed by DNA repair machinery, leading to potent antitumor responses.
• Establishes a new paradigm for leveraging STING activation in cancer immunotherapy.