Targeting the PRMT1-cGAS-STING signaling pathway to enhance the anti-tumor therapeutic efficacy
Daoyuan Huang1, Abdol-Hossein Rezaeian1, Jingchao Wang1
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
Activating innate immune signaling in tumor cells to enhance anti-tumor immunity and increase T cell-mediated killing is the core objective of tumor immunotherapy. PRMT1, one of the most crucial PRMTs, plays a critical role in tumor progression and innate immunity. Recent research revealed that PRMT1 can inhibit the enzymatic activity of cGAS in part through PRMT1-mediated Arg methylation, thereby suppressing the anti-tumor immune response of cells. As such, inhibiting or knocking down PRMT1 can synergistically enhance the efficacy of anti-PD-1 immunotherapy by activating the cGAS-STING signaling pathway. Here, we provide a comprehensive description of the two key signaling components, PRMT1 and cGAS, in the PRMT1-cGAS-STING signaling pathway for therapeutic intervention to augment anti-tumor immunity. By understanding the specific physiological functions and regulatory mechanisms of PRMT1, as well as the extensive post-translational modifications (PTMs) of cGAS, we have identified several compounds and drugs that can directly target PRMT1 or cGAS, and/or indirectly target PRMT1 upstream regulators or cGAS-post-translational modifying enzymes as potential means to activate the cGAS-STING signaling pathway. However, further investigation is needed on the efficacy of combining this pathway activation with anti-PD1 therapy. This review suggests that targeting the PRMT1-cGAS-STING pathway with immune checkpoint inhibitors is likely a promising approach in tumor immunotherapy.
Insights
Inhibiting PRMT1 activates the cGAS-STING pathway, enhancing anti-tumor immunity and T cell responses. This approach shows promise for augmenting cancer immunotherapy when combined with immune checkpoint inhibitors.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Activating innate immune signaling in tumor cells is crucial for effective anti-tumor immunity and T cell-mediated killing.
- PRMT1, a key protein arginine methyltransferase, influences tumor progression and innate immunity.
- PRMT1 can suppress anti-tumor immune responses by inhibiting cGAS enzymatic activity via Arg methylation.
Purpose of the Study:
- To comprehensively describe PRMT1 and cGAS in the PRMT1-cGAS-STING pathway for therapeutic intervention.
- To identify compounds targeting PRMT1 or cGAS to activate the cGAS-STING signaling pathway.
- To explore the potential of targeting this pathway to augment anti-tumor immunity.
Main Methods:
- Review of signaling components PRMT1 and cGAS within the PRMT1-cGAS-STING pathway.
- Analysis of PRMT1 physiological functions and regulatory mechanisms.
- Investigation of cGAS post-translational modifications (PTMs) and their impact.
Main Results:
- Inhibiting or knocking down PRMT1 enhances anti-PD-1 immunotherapy efficacy by activating the cGAS-STING pathway.
- Compounds targeting PRMT1, cGAS, or related enzymes were identified as potential activators of the cGAS-STING pathway.
- The combination of PRMT1-cGAS-STING pathway activation with anti-PD1 therapy requires further investigation.
Conclusions:
- Targeting the PRMT1-cGAS-STING pathway is a promising strategy to augment anti-tumor immunity.
- Activating this pathway can synergistically enhance the efficacy of anti-PD-1 immunotherapy.
- Further research is needed to validate the combination of PRMT1-cGAS-STING pathway activation with immune checkpoint inhibitors in cancer treatment.
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