For many tumor indications optimal treatment selection often depends on the presence of specific tumor biomarkers such as PDL1. Unfortunately, due to the dynamic nature of cancer, very often these predictive biomarkers are not consistently present and today tumor heterogeneity and immune escape mechanisms still represent one of the main causes of therapeutic trial failure. Given the essential role of innate immunity in cancer immune surveillance, tremendous effort has therefore been focused on these innate immune pathways that can be pharmacologically modulated to improve the clinical outcome of checkpoint inhibitors (e.g., anti-PD-1/PD-L1 therapies). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has now been recognized in host defense against cancers1.
Cyclic GMP-AMP (cGAMP) synthase (cGAS), a cytoplasmic double-stranded DNA sensor is known to play a key role in Type-1 interferon and inflammatory responses via a Stimulator of Interferon Genes (STING)-dependent signaling pathway. While this pathway has been demonstrated to have a regulatory role in (for example) autoimmune diseases, antiviral defense and neurological disorders, in recent years there is increasing evidence that the cGAS-STING pathway is also closely related to the modulation of cancer, by promoting an antitumor environment through activation of T cells, dendritic cells, and natural killer cells. Much research has therefore focused on the intimate role that the cGAS-STING pathway has in regulating various aspects of the well described Chen and Mellman Cancer-Immunity Cycle that includes tumor antigen release, antigen presentation, the priming and activation of T cells, the trafficking and infiltration of T cells into tumor tissues, and the recognition and killing of tumor cells by T cells. Since tumors often evade the immune system by suppressing some of these immune responses, activation of the STING pathway therefore can enhance the necessary recognition of tumors by the immune system, making them more "visible" to appropriate immune cells.
Recent effort has focused on the development of STING agonists, a new class of agents that activate the immune response to improve tumor control. By stimulating the production of interferons and other immune-stimulating molecules, these STING agonists can help to create a more favorable environment for the immune system to attack cancer cells. In the past, effective STING agonist design was hampered by low cytosol delivery derived from its physiochemical properties such as electronegativity and hydrophilicity. This low intracellular uptake efficiency resulted in insufficient presentation efficiency of STING agonists to antigen-presenting cells (APCs). Further, enzymatic degradation of STING agonists in blood circulation unfortunately led to a fast clearance rate and short half-life of potential STING agonists and significantly confined their clinical translation and application. Today, a wide range of published preclinical experiments, translational data, and new ongoing clinical trials currently support the therapeutic use of an updated STING agonist design with particular emphasis on versatile nano-delivery systems. Numerous clinical trials are also investigating STING agonists alone or in combination with other therapies like checkpoint inhibitors to enhance their efficacy against various cancers. Researchers are also exploring the use of STING pathway modulation in combination with radiation or chemotherapy to increase the effectiveness of these traditional treatments. Indeed, early phase trials highlighted at AACR 20242 and ASCO20243 have demonstrated the efficacy of STING agonists and revealed new mechanistic insights. A thorough understanding of the temporal and spatial controls in which the cGAS–STING pathway exerts its role on tumors will improve our ability to appropriately target this pathway and ensure adequate patient selection.
Spatial resolution is key to our understanding of not just cellular function, but also linking biologically relevant interactions to specific cell types. At this year’s AACR2024, one of several posters from NeoGenomics Laboratories sought to characterize STING-interferon expression within the tumor microenvironment (TME) of a variety of tumor indications including melanoma and head & neck squamous cell carcinoma using a novel integrated MultiOmyx™ -RNAscope™ platform4. Briefly, quantification and analysis using the proprietary MultiOmyx analytics pipeline examined the spatial distribution and expression levels of key STING pathway induced cytokines to elucidate the dynamic communication of signaling molecules and their localization within specific cell populations. Use of spatial insight was also effectively applied in a recent paper utilizing a novel STING agonist to selectively target mouse prostate tumors during androgen deprivation therapy (ADT)5. Using our MultiOmyx platform and analytics pipeline the group showed that ADT induced the perivascular accumulation of pro-tumoral tumor associated macrophages (TAMs) in prostate tumors prior to the onset of castrate-resistant prostate cancer (CRPC). The group then went on to selectively induce these TAMs to express a potent immunostimulant, interferon beta (IFNβ) to potentially stimulate antitumor immunity and delay CRPC using a novel antibody-coated, lipid nanoparticles (LNPs) to target a STING agonist, 2′3′-cGAMP (cGAMP), to the perivascular TAMs in mouse prostate tumors during ADT, showcasing that STING agonists could extend the treatment window for ADT and potentially limit the metastatic spread of disease.
The impact of the cGAS-STING pathway on cancer outcomes clearly depends on various factors, including tumor type, the host’s immune profile, specific cell types activated, the therapeutic approach employed, and the degree of cGAS-STING activation. By improving our ability to dissect the complexity of the cancer ecosystem, including the cells and pathways involved together with the use of novel approaches such as spatial insight, utility of STING agonists within cancer immunotherapy truly represents a promising avenue for enhancing cancer treatment efficacy and importantly also has the potential to revolutionize patient outcomes.
References
1.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1399926/full
2. aacrjournals.org/cancerres/article/84/6_Supplement/7481/736115/Abstract-7481-The-allosteric-STING-agonist-CRD3874
3. ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS2690
4. aacrjournals.org/cancerres/article/84/6_Supplement/94/739330
5. jitc.bmj.com/content/12/7/e009368