The cGAS–STING signaling pathway has emerged as a major focus in cancer immunotherapy because it stimulates interferon production and enhances antitumor immune responses. However, despite strong preclinical promise, clinical outcomes of STING agonists have been inconsistent, with many tumors showing limited responsiveness. Most previous studies emphasized immune-microenvironment regulation while overlooking tumor-intrinsic mechanisms that might determine therapeutic sensitivity. In addition, clinicians lack reliable biomarkers to predict which patients may benefit from STING-based therapies. The biological reasons underlying differential tumor responses therefore remain unclear. Based on these challenges, a deeper investigation into tumor-cell-intrinsic mechanisms of STING activation is required.
Researchers from the Department of Bio-Therapeutic at the First Medical Center of the Chinese PLA General Hospital, in collaboration with colleagues from the Fifth Medical Center of the Chinese PLA General Hospital, Peking University School of Life Sciences, and Changping Laboratory (Beijing, China), reported their findings (DOI: 10.20892/j.issn.2095-3941.2025.0326)in 2026 in Cancer Biology & Medicine. The study demonstrates that STING agonists exert potent antitumor effects against nervous system tumors, including neuroblastoma and glioblastoma, by activating a tumor-intrinsic signaling pathway. Through integrated cellular, animal, and bioinformatics analyses, the researchers identified a STAT1-dependent mechanism that upregulates HMGN2 and drives tumor cell apoptosis.
The researchers first screened multiple tumor cell types to determine sensitivity to STING agonists. Proliferation assays revealed that neural-origin tumors responded strongly, while several non-neural cancers showed minimal effects. In mouse tumor models, treatment with the small-molecule agonist SR-717 significantly suppressed tumor growth, even under immune-deficient conditions, indicating that antitumor activity was partly independent of immune cells.To uncover the mechanism, RNA sequencing identified genes consistently upregulated after STING activation, highlighting HMGN2 as a key candidate. Molecular experiments confirmed that STING stimulation increased HMGN2 expression at both transcriptional and protein levels. Overexpression of HMGN2 alone induced strong apoptosis, whereas knockout of HMGN2 abolished the therapeutic effect of STING agonists, demonstrating its essential role.Further mechanistic studies revealed that STAT1 acts as a transcriptional regulator linking STING activation to HMGN2 expression. Chromatin immunoprecipitation assays showed STAT1 binding directly to the HMGN2 promoter, forming a STING–STAT1–HMGN2 signaling axis that drives tumor cell death. Bioinformatic analyses of public cancer datasets additionally showed that higher HMGN2 expression correlates with improved survival across multiple malignancies, reinforcing its potential clinical importance.
According to the researchers, the findings shift the understanding of STING agonists from purely immune modulators to direct regulators of tumor cell fate. By identifying HMGN2 as a central mediator, the study explains why some tumors respond strongly while others remain resistant. The team noted that recognizing tumor-intrinsic signaling mechanisms could help refine patient selection and optimize therapeutic design, enabling STING-based treatments to achieve more predictable and durable outcomes in clinical oncology.
The discovery of the STING–STAT1–HMGN2 axis opens new opportunities for precision immunotherapy. Measuring HMGN2 expression may allow clinicians to identify patients most likely to benefit from STING agonists, improving treatment efficiency while reducing unnecessary exposure to ineffective therapies. Beyond nervous system tumors, the pathway may represent a broader therapeutic principle applicable across multiple cancer types. Future research may explore combination therapies that enhance HMGN2 activation or restore pathway sensitivity in resistant tumors. Ultimately, these findings provide a framework for transforming STING agonists from experimental immunotherapies into clinically guided, mechanism-based cancer treatments.
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References
DOI
10.20892/j.issn.2095-3941.2025.0326
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0326
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 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).