STING Agonists and How to Reach Their Full Potential in Cancer Immunotherapy

Abstract

As cancer continues to rank among the leading causes of death, the demand for novel treatments has never been higher. Immunotherapy shows promise, yet many solid tumors such as pancreatic cancer or glioblastoma remain resistant. In these, the "cold" tumor microenvironment with low immune cell infiltration and inactive anti-tumoral immune cells leads to increased tumor resistance to these drugs. This resistance has driven the development of several drug candidates, including stimulators of interferon genes (STING) agonists to reprogram the immune system to fight off tumors. Preclinical studies demonstrated that STING agonists can trigger the cancer immunity cycle and increase type I interferon secretion and T cell activation, which subsequently induces tumor regression. Despite promising preclinical data, biological and physical challenges persist in translating the success of STING agonists into clinical trials. Nonetheless, novel combination strategies are emerging, investigating the combination of these agonists with other immunotherapies, presenting encouraging preclinical results. This review will examine these potential combination strategies for STING agonists and assess the benefits and challenges of employing them in cancer immunotherapy.

Keywords: STING agonists; cancer; immunotherapy; tumor microenvironment; tumor resistance.

Figure 1

Summary of the cGAS‐STING pathway. Self‐DNA from mitochondria or derived from chromosomal instability (CIN) through micronuclei or foreign double‐stranded DNA (dsDNA) from viruses, bacteria, or cancer can trigger the recognition by cyclic GMP‐AMP synthase (cGAS). The second messenger cyclic guanosine monophosphate‐adenosine monophosphate (cGAMP) binds to the stimulator of interferon genes (STING) on the endoplasmatic reticulum, initiating dimerization. Following TANK‐binding kinase 1 (TBK1) phosphorylation after STING translocation to the Golgi apparatus, TBK1 transphosphorylates interferon regulatory factor 3 (IRF3), which dimerizes and translocates into the nucleus and activates the transcriptional activation of type I interferons (IFNs, orange arrows). Type I IFNs can leave the cell and then bind to the interferon‐α/β receptor (IFNAR) on other immune cells, creating a positive feedback loop. The non‐canonical NF‐κB pathway activates the secretion of inflammatory cytokines such as IL‐6 (turquoise arrows). In addition, cGAMP can enter cells via transporters (P2×7, LRRC8A:C/E) or gap junctions from bystander cells. Red arrows indicate DNA sources activating the cGAS‐STING pathway, while green arrows show cGAMP sources. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) degrades exogenous cGAMP. Figure created with BioRender.

Figure 2

STING activation and suppression within the cancer immunity cycle. Antigens are released in the tumor microenvironment (TME), triggering dendritic cell (DCs) activation in tumor‐draining lymph nodes. These DCs then present tumor antigens to T cells, activating them. STING activation results in ICAM‐1 and E‐selectin upregulation and secretion of chemokines like CXCL9 and CXCL10, enhancing the trafficking of immune cells like T cells or natural killer (NK) cells into the TME. Inside the tumor, STING activation boosts NK cells, and increases CD4⁺ and CD8⁺ T cells while decreasing regulatory T cells (T _regs) and myeloid‐derived suppressor cells (MDSCs). The rise in cytotoxic CD8⁺ T cells promotes tumor cell death, which in turn increases the release of tumor antigens, perpetuating the cancer immunity cycle. However, STING activation in the TME can lead to PD‐1 upregulation on T cells, while ENPP1 can degrade cGAMP into adenosine, inhibiting T cell function. Tumor cells often modify STING via methylations through KDM5 or inhibit STING activation via SMARCAL or mutated p53, blocking the STING‐TBK1‐IRF3 complex. Figure created with BioRender.

Figure 3

Number of publications in Pubmed when searching for "STING agonist" and "cancer" over the last nine years. Checked in February 2025. Both review and research articles are included.

Figure 4

Potential combination strategies for STING agonists to combat potentially immunosuppressive effects. To counteract T cell overactivation, checkpoint inhibitors can be used, while PI3Kγ inhibitors may alleviate NK cell suppression induced by the STING agonist. The combination of DNA methylase (DNMT) inhibitors and STING agonists can help to reverse tumor‐mediated STING silencing. Inhibiting the non‐canonical (NC) nuclear factor kappa B (NF‐κB) pathway together with a STING agonist may enhance the anti‐tumoral type I interferon response. The use of transforming growth factor beta (TGF‐β) inhibitors can reverse immune suppression on immune cells induced by STING activation in the tumor microenvironment. To target T cell inhibition in the TME, cyclooxygenase 2 (COX2) and indoleamine 2,3‐dioxygenase (IDO) inhibitors can be useful in combination with STING agonists. Nanocarriers and antibody‐dependent conjugates (ADCs) can deliver STING agonists in a systemic setting directly to the tumor, overcoming the need for intratumoral injection. Figure created with BioRender.

Figure 5

The benefits and limitations of STING agonists for cancer immunotherapy. STING agonists can transform a pro‐tumoral “cold” tumor microenvironment (TME) into a “hot” immunogenic TME through the activation of antigen‐presenting cells (APCs) via type I interferons (IFNs) resulting from STING activation. This facilitates the activation of CD4⁺ and CD8⁺ T cells, which subsequently infiltrate the TME, leading to increased cancer cell death. Moreover, STING agonists have been shown to promote the infiltration of natural killer (NK) cells and the turnover of M2 pro‐tumoral macrophages into M1 anti‐tumoral macrophages, the reduction of regulatory T cells and normalize the vasculature. However, STING agonists can also elevate immunosuppressive factors, augmenting PD‐L1 expression, driving T cell exhaustion, promoting the differentiation of myeloid‐derived suppressor cells, and raising levels of regulatory B cells (B _regs), which may lead to clinical side effects such as cytokine release syndrome or liver toxicity. Green arrows indicate positive effects and red arrows indicate negative effects. Figure created with BioRender.