Mastering the STING Pathway for Enhanced Immunotherapy

Scientists have developed a new approach to cancer immunotherapy by controlling the STING pathway, which could potentially increase the rate and durability of immunotherapy responses. The STING pathway is an evolutionarily ancient pattern recognition receptor that has been implicated as a master regulator of the cancer-immunity cycle. However, clinical trials of STING agonists in cancer patients have yielded disappointing results due to major challenges in STING agonist design and delivery.

To address this, a team of researchers has developed a genetically engineered "universal" STING agonist (uniSTING) that represents a fundamentally new approach. The uniSTING is designed to tetramerize outside of the endoplasmic reticulum, allowing it to recruit TBK1 and activate IRF3, but without engaging the NF-κB axis. This results in an innate immune response shaped primarily by IRF3 signalling, characterized by IFN-Is and interferon-stimulated genes with minimal induction of NF-κB-driven proinflammatory cytokines.

The team has also packaged mRNA encoding uniSTING into a previously described lipid nanoparticle (LNP) formulation containing the bioreducible ionizable lipid COATSOME SS-OP. This formulation increases gene expression compared to LNPs fabricated using the conventional MC3 ionizable lipid and biased delivery to cancer cells over infiltrating immune cells. The authors primarily utilized an intratumoural administration route, demonstrating superior antitumour efficacy compared to CDN STING agonists in models of lung cancer, melanoma, and breast cancer.

The uniSTING can be employed universally, as it can activate STING signalling in cells that otherwise lack functional STING protein. This is important because some cancer cells silence or downregulate STING to evade the immune system. The recent advances in LNP design provide an opportunity to develop and optimize the nanocarrier for delivery of uniSTING mRNA to extrahepatic tumour tissue.

The work by Wang and Li et al. challenges us to think beyond conventional nanoscale design paradigms and more deeply into how to better control the cell biology that underlies responses to emerging therapeutics. As STING agonists continue to enter clinical evaluation, it will also be important to consider if potently activating the NF-κB axis is detrimental.

The research was published in Nature Nanotechnology and is available at <https://doi.org/10.1038/s41565-024-01624-2>

Source: Wang, Y. et al. Controlling the STING pathway to improve immunotherapy. Nat. Nanotechnol. https://doi.org/10.1038/s41565-024-01624-2 (2024).