Exogenous non-coding dsDNA-dependent trans-activation of phagocytes augments anti-tumor immunity

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Stimulator of interferon genes (STING) signaling is crucial for anti-microbial and anti-tumor immunity.
• Cancer cells often evade immune surveillance by exhibiting defective STING signaling.
• Restoring STING pathway function presents a potential therapeutic strategy against cancer.

Purpose of the Study:

• To investigate if recombinant herpes simplex viruses (rHSVs) expressing STING pathway components can restore intrinsic STING signaling in cancer cells.
• To evaluate the anti-tumor efficacy of these rHSVs.
• To explore alternative strategies using dsDNA nanoparticles to activate STING signaling for cancer treatment.

Main Methods:

• Creation of rHSVs engineered to express STING and/or cGAS.
• Assessment of rHSV replication efficiency and in vivo anti-tumor activity.
• Administration of non-coding dsDNA species via nanoparticles to activate STING signaling in phagocytes.
• Evaluation of nanoparticle-mediated STING activation in combination with established cancer therapies.

Main Results:

• rHSVs expressing STING and/or cGAS showed inefficient replication but retained significant in vivo anti-tumor activity.
• The anti-tumor effects of rHSVs were independent of oncolytic activity and extrinsic STING signaling in phagocytes.
• Nanoparticles delivering non-coding dsDNA effectively activated phagocytes, mimicking virotherapy effects.
• dsDNA nanoparticles augmented the efficacy of checkpoint inhibition and radiation therapy in cancer treatment.

Conclusions:

• Restoring intrinsic STING signaling via rHSVs or dsDNA nanoparticles can confer anti-tumor activity.
• Virotherapy's anti-tumor mechanisms can be mimicked by dsDNA nanoparticles, offering alternative therapeutic strategies.
• This research provides insights into virotherapeutic mechanisms and presents novel approaches to enhance cancer treatment efficacy.