STING, or Stimulator of Interferon Genes, is a protein in the body’s innate immune system. It functions as a sensor within cells, detecting DNA found outside its usual location in the nucleus or mitochondria. Recent research highlights STING’s complex involvement in cancer, demonstrating both beneficial and detrimental effects on tumor progression, in addition to its roles in inflammation and infection response.
How STING Protects the Body
STING functions as a “danger sensor” within cells, monitoring the intracellular environment for unusual DNA. Normally, DNA is confined to the cell’s nucleus or mitochondria; its presence in the cytoplasm signals a potential threat like a viral or bacterial infection, or cell damage. When cyclic GMP-AMP synthase (cGAS) detects this misplaced DNA, it produces cyclic GMP-AMP (cGAMP).
This cGAMP directly binds to STING, which is located on the endoplasmic reticulum. The binding causes STING to undergo a structural change and move to the Golgi apparatus. This relocation activates a cascade of signaling events involving proteins such as TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3).
The activated IRF3 then travels into the cell’s nucleus, initiating the production of immune signaling molecules called type I interferons (IFN-I). These interferons alert and mobilize various immune cells, including dendritic cells and T cells, to identify and eliminate the source of danger, whether an infection or abnormal cells.
STING’s Complex Role in Cancer
STING’s influence on cancer is multifaceted, exhibiting both tumor-suppressive and tumor-promoting effects. Its impact varies depending on the cellular context and tumor characteristics.
Tumor-Suppressive Effects
When STING is activated within cancer cells or immune cells in the tumor environment, it can trigger anti-tumor immunity. This activation can lead to direct killing of cancer cells or recruit and activate immune cells to destroy the tumor. STING activation promotes the maturation of antigen-presenting cells, such as dendritic cells, which educate T cells to target tumor-specific antigens. These activated T cells then infiltrate the tumor and contribute to its destruction.
The STING pathway can also enhance the activation and function of natural killer (NK) cells, immune cells capable of directly killing cancer cells. In various mouse tumor models, STING activation improves anti-tumor immunity by increasing type I interferon expression, which promotes T cell responses. In specific cancers like colorectal tumors, loss of STING in tumor cells can accelerate tumor growth, suggesting its suppressive function.
Tumor-Promoting Effects
Despite its anti-tumor capabilities, STING activation can, in certain situations, promote tumor growth. Chronic or uncontrolled STING activation can lead to persistent inflammation, creating an environment favorable for cancer cell proliferation and survival. This sustained inflammatory state can foster mechanisms that suppress the anti-tumor immune response. For example, chronic type I interferon signaling, a downstream effect of STING activation, has been linked to immune suppression and the promotion of metastasis in some contexts.
STING activation can also induce the expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO-1). These molecules inhibit T cell activation and promote immune evasion by tumors. The outcome of STING activation depends on factors like the specific cell type, cancer type, and the tumor’s microenvironment.
Unlocking STING for Cancer Treatment
Harnessing the STING pathway’s immune-activating properties holds promise for novel cancer therapies. Researchers are exploring ways to enhance the body’s natural defenses against tumors.
STING Agonists
STING agonists are drugs designed to intentionally activate the STING pathway. This approach leverages the immune system to fight cancer by inducing a robust anti-tumor immune response. Many agonists are synthetic cyclic dinucleotides, such as 2’3′-cGAMP, which directly bind to and activate STING.
Preclinical studies show that intratumoral injection of STING agonists can lead to tumor regression in various mouse models, including melanoma, breast cancer, and lung cancer. This activation promotes type I interferon production and other pro-inflammatory cytokines, which activate and mature dendritic cells and T cells, enhancing anti-tumor immune responses. Challenges like potential toxicity and effective delivery methods remain considerations for clinical translation.
Combination Therapies
STING activators are being investigated in combination with other established cancer treatments to create a more potent anti-tumor response. The inflammatory cytokines induced by STING agonists can remodel the tumor microenvironment, making it more receptive to other immunotherapies. For example, combining STING agonists with immune checkpoint inhibitors has shown enhanced tumor remission and prolonged survival in preclinical models compared to monotherapy. This combination aims to activate both innate and adaptive immune systems.
STING agonists are also being explored alongside conventional therapies like chemotherapy and radiation therapy. Chemotherapy and radiation can cause DNA damage in tumor cells, leading to the release of DNA fragments into the cytoplasm, which can then activate the cGAS-STING pathway. Combining these DNA-damaging agents with STING agonists can amplify the immune response, turning “cold” tumors, which have minimal immune cell infiltration, into “hot” tumors characterized by a robust immune presence. Ongoing research aims to optimize dosing, delivery methods, and combination strategies to maximize therapeutic benefits while minimizing potential side effects.