Immune checkpoint inhibitors (ICIs) have transformed cancer care, yet only a subset of patients benefit. A major barrier is tumor microenvironment (TME) heterogeneity: “hot” tumors are enriched with cytotoxic T lymphocytes (CTLs) and respond better, while “cold” tumors lack T-cell infiltration or are shielded by immunosuppressive barriers. The cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway senses cytosolic DNA and bridges innate and adaptive immunity, but its effects are context-dependent—acute signaling can be protective, while chronic signaling can promote tumor progression. First-generation STING agonists have also faced poor pharmacokinetics, systemic toxicity, and limited intratumoral delivery. Given these challenges, there is a need for in-depth research on how to precisely modulate cGAS-STING signaling across different TME phenotypes.
Researchers from Tianjin University of Traditional Chinese Medicine, Tianjin Medical University Cancer Institute & Hospital, and Tianjin First Central Hospital published (DOI: 10.20892/j.issn.2095-3941.2026.0058) the review in Cancer Biology & Medicine. The article examines the molecular activation of the cGAS-STING pathway, its dual antitumor and protumor roles, and strategies to convert cold tumors into hot tumors. It also evaluates clinical trial bottlenecks and emerging delivery technologies, including antibody-drug conjugates (ADCs), immune-stimulating antibody conjugates (ISACs), nanoparticle systems, bacterial vectors, and exosomes.
The review emphasizes that cGAS-STING is not simply a DNA sensor but a multilayered signaling hub. It distinguishes tumor-intrinsic STING signaling, which is highly time- and dose-dependent, from host innate immune cell signaling in dendritic cells (DCs) and macrophages, which can amplify durable adaptive immunity. After cGAS binds cytosolic double-stranded DNA (dsDNA), it produces 2′3′-cyclic GMP-AMP (2′3′-cGAMP), which activates STING on the endoplasmic reticulum (ER). STING then traffics to the Golgi, where palmitoylation and oligomerization facilitate TANK-binding kinase 1 (TBK1) recruitment and subsequent interferon regulatory factor 3 (IRF3) activation, driving type I interferon (IFN-I) and inflammatory cytokine production. Acute activation can promote DC maturation, antigen cross-presentation, CD8⁺ T-cell priming, and natural killer (NK) cell activity. However, chronic activation driven by chromosomal instability (CIN) can promote sustained nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and immunosuppression, while ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)-mediated extracellular cGAMP hydrolysis can further facilitate immune evasion and metastasis. The authors propose mapping STING modalities to TME states: vaccines or oncolytic viruses for immune-desert tumors; nanotechnology, vascular normalization, and cancer-associated fibroblast (CAF) reprogramming for immune-excluded tumors; ADCs/ISACs plus IDO inhibitors for myeloid-suppressed tumors; and STING agonists plus ICIs or adoptive cell therapy (ACT) for exhausted-inflamed tumors.
The authors said the field is moving beyond one-size-fits-all STING activation. They said the key is not simply turning the pathway on, but turning it on in the right place, at the right time, and in the right cells. They explained that acute, tumor-localized STING signaling can license dendritic cells and recruit effector T cells, while chronic or systemic activation may trigger feedback that suppresses immunity. They said next-generation delivery systems could help separate intratumoral benefit from systemic toxicity. According to the authors, biomarker-driven patient selection and TME-phenotype mapping will be essential for translating STING-targeted therapies into durable clinical benefit.
If validated clinically, this framework could guide trial design, combination regimens, and patient stratification. Matching STING agonists and delivery platforms to immune-desert, immune-excluded, myeloid-suppressed, and exhausted-inflamed TMEs may improve tumor-specific delivery and reduce off-target inflammation. Antibody-drug conjugates (ADCs), immune-stimulating antibody conjugates (ISACs), nanoparticles, bacterial vectors, and exosomes could help overcome poor pharmacokinetics and extracellular degradation. Combining STING activation with ICIs, cancer vaccines, ACT, IDO inhibitors, or oncolytic viruses may extend benefit to patients whose tumors resist current immunotherapies. The authors also stress that safety, dosing, scheduling, and human TMEM173 (transmembrane protein 173) polymorphisms must be addressed. Ultimately, this precision approach could expand the population benefiting from immunotherapy and support next-generation immuno-oncology.
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References
DOI
10.20892/j.issn.2095-3941.2026.0058
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2026.0058
Funding Information
This work was supported by the National Natural Science Foundation of China (Grant No. 82504823), Natural Science Foundation of Tianjin (Grant Nos. 25JCQNJC00590 and 25JCLMJC00560) and Tianjin Key Medical Discipline Construction Project (Grant No. TJYXZDXK-3-003A).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).