Stimulators of interferon genes (STING) agonists are emerging as a promising avenue in the world of cancer immunotherapy. STING, a protein that detects foreign nucleic acids, has a striking resemblance to Toll-like receptors (TLR) agonists, and it shares parallels with the historical significance of Coley’s toxins. These agonists kickstart an initial innate immune response by triggering the secretion of immune-stimulating cytokines, particularly interferon. This initial response is crucial in priming T cells, the frontline soldiers of the immune system, for action. In the realm of approved immunotherapies like anti-PD-1 and anti-CTLA-4, the recruitment and activation of T cells within the local tumor environment are essential for success. Hence, STING and TLR agonists have garnered considerable attention, as they play a pivotal role in initiating this critical immune response, laying the foundation for more specific and durable anti-cancer immunity.

Dr. Glen Barber’s discovery of STING in 2008 shed light on the protein’s role in countering viral infections, showcasing its significance in our immune defense. Further research revealed that cyclic diguanylate monophosphate, a molecule found in bacteria, could activate STING, setting off an innate immune response. By understanding this mechanism, scientists have developed synthetic cyclic dinucleotides (CDNs) and other small molecules to stimulate STING, an area of ongoing research. Intriguingly, combining TLR and STING agonists in animal studies has shown a synergistic effect, enhancing the anti-cancer immune response. While the future of STING agonists in cancer immunotherapy looks promising, they are not as developed as TLR agonists at present. The focus remains on intra-tumoral injection, which seems to be the most effective administration method, with potential for even better outcomes when combined with agents like OX40 agonists.

It’s important to note that there are both human and mouse versions of STING, which became evident when the promising results of a mouse-specific STING agonist, DMXAA, did not translate well in human trials. This emphasizes the need to find molecules that can activate STING in both humans and mice. While researchers are exploring alternate administration methods, the safety and efficacy of intra-tumoral injection remain compelling. High doses of STING agonists can paradoxically lead to T cell death, making systemic administration a tricky endeavor. An exciting recent development is the identification of α-Mangostin as a human STING agonist, which may hold the potential to convert tumor-protecting macrophages into tumor-attacking ones. Derived from the fruit of the mangosteen tree, this natural source of a potentially significant cancer medication is a promising discovery. However, it’s unclear whether simply consuming the fruit would provide the same benefits. There’s evidence that oral mangostin extracts may have undesirable effects on the microbiome, increasing inflammation and reducing bacterial diversity, which further underscores the advantages of direct injection in tumor regions.

STING agonists are illuminating a path forward in cancer immunotherapy, offering hope for a more effective and targeted approach to treating cancer. As research continues to unfold, these agonists may play a crucial role in overcoming immune resistance and enhancing the body’s natural defenses against cancer.

Reference: Jason R. Williams, 15 Oct 2019, The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients’ Lives, https://williamscancerinstitute.com/the-immunotherapy-revolution