Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The stimulator of interferon genes (STING) pathway is crucial for cancer immunity and tumor microenvironment modulation, making it a key target for cancer immunotherapy.
• While STING agonists show promise, most are in early clinical trials, highlighting the need for readily available small molecules.
• ABT-199 has been identified as a small molecule capable of activating the STING pathway to enhance immunotherapeutic effects.

Purpose of the Study:

• To investigate the activation of the STING signaling pathway by ABT-199 in colorectal cancer cells.
• To evaluate the in vivo therapeutic effects of ABT-199, alone and in combination with anti-PD-L1 therapy.
• To elucidate the molecular mechanism underlying ABT-199-induced STING activation, focusing on VDAC1 oligomerization and mtDNA release.

Main Methods:

• Assessed STING pathway activation via phosphorylation of STING, TBK1, and IRF3, and IFN-I signaling.
• Evaluated in vivo efficacy in mice with subcutaneous tumors using ABT-199 and anti-PD-L1 combination.
• Utilized flow cytometry, ELISA, immunofluorescence, qPCR, chemical cross-linking, co-immunoprecipitation, and CRISPR/Cas9 to investigate molecular mechanisms.

Main Results:

• ABT-199 significantly activated the STING pathway in colorectal cancer cells, increasing TBK1/IRF3 phosphorylation and chemokine expression (CCL5, CXCL10).
• ABT-199 promoted antitumor immunity by enhancing cytotoxic T-cell infiltration and synergized with anti-PD-L1 therapy.
• ABT-199 induced STING activation via cytoplasmic mtDNA release, mediated by VDAC1 oligomerization disrupting the BCL-2 interaction.

Conclusions:

• ABT-199 serves as a ready-to-use small molecule for STING activation, offering a new avenue for cancer immunotherapy.
• The study reveals ABT-199's mechanism of action, involving VDAC1-mediated mtDNA release and subsequent STING pathway activation.
• These findings provide a strong theoretical foundation for utilizing ABT-199 in clinical cancer immunotherapy strategies.