Context-dependent cGAS-STING signaling in solid tumors: biological determinants, clinical implications, and biomarker-guided therapeutic strategies
- 1The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)
Abstract
Stimulator of interferon genes (STING) agonists are intended to convert cytosolic DNA sensing into productive antitumor immunity, yet their biological effects vary substantially among tumors. Outcomes depend on the cellular compartment engaged, the amplitude and duration of signaling, tumor genotype, the immune architecture of the tumor microenvironment, and drug distribution. A critical distinction must therefore be made between chronic endogenous, tumor-cell-intrinsic cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, as may occur in chromosomally unstable tumors, and controlled pharmacological STING agonism. The former can sustain maladaptive inflammatory programs in selected experimental settings, whereas the latter can be delivered transiently and may preferentially activate dendritic cells and other host immune compartments. This narrative review examines canonical STING-TBK1-IRF3/type I interferon signaling and alternative chronic outputs; relates these mechanisms to chromosomal instability, mismatch-repair status, immune surveillance, and immune checkpoint blockade; and evaluates early clinical experience with intratumoral STING agonists. Available trials demonstrate target engagement and generally manageable toxicity, but efficacy has been limited or heterogeneous. Mismatch-repair status, tumor mutational burden, chromosomal instability, baseline interferon activity, STING pathway competence, immune-cell topology, and delivery feasibility should therefore be considered components of a candidate composite biomarker strategy rather than validated predictors. By contrast, STING inhibition in chromosomal-instability-high tumors remains a promising preclinical hypothesis, not an established treatment. Prospective, compartment-resolved biomarker studies are needed to match agonists, delivery systems, combination regimens, or inhibitory approaches to the appropriate tumor state.
Related
- Temperature-Dependent Development, Survival, and Population Growth of Novius penicillioides: Implications for Biological Control of Icerya jacobsoni Under Climate Warming
- Yield determinants in rice under organic and conventional production systems: Implications for selection strategies
- Information coding strategies in biological reservoir computing for multiclass time-series classification
- Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy
- Dendritic cell diversity and dysfunction in cancer: implications for immunotherapy and therapeutic targeting
BibTeX
@article{wang2026contextdependent,
title = {{Context-dependent cGAS-STING signaling in solid tumors: biological determinants, clinical implications, and biomarker-guided therapeutic strategies}},
author = {Zhenru Wang and Yuerufei Yu and Ying Zhu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1954279},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954279/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Context-dependent cGAS-STING signaling in solid tumors: biological determinants, clinical implications, and biomarker-guided therapeutic strategies
AU - Zhenru Wang
AU - Yuerufei Yu
AU - Ying Zhu
PY - 2026
DA - 2026/10/19
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1954279
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954279/full
AB - Stimulator of interferon genes (STING) agonists are intended to convert cytosolic DNA sensing into productive antitumor immunity, yet their biological effects vary substantially among tumors. Outcomes depend on the cellular compartment engaged, the amplitude and duration of signaling, tumor genotype, the immune architecture of the tumor microenvironment, and drug distribution. A critical distinction must therefore be made between chronic endogenous, tumor-cell-intrinsic cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, as may occur in chromosomally unstable tumors, and controlled pharmacological STING agonism. The former can sustain maladaptive inflammatory programs in selected experimental settings, whereas the latter can be delivered transiently and may preferentially activate dendritic cells and other host immune compartments. This narrative review examines canonical STING-TBK1-IRF3/type I interferon signaling and alternative chronic outputs; relates these mechanisms to chromosomal instability, mismatch-repair status, immune surveillance, and immune checkpoint blockade; and evaluates early clinical experience with intratumoral STING agonists. Available trials demonstrate target engagement and generally manageable toxicity, but efficacy has been limited or heterogeneous. Mismatch-repair status, tumor mutational burden, chromosomal instability, baseline interferon activity, STING pathway competence, immune-cell topology, and delivery feasibility should therefore be considered components of a candidate composite biomarker strategy rather than validated predictors. By contrast, STING inhibition in chromosomal-instability-high tumors remains a promising preclinical hypothesis, not an established treatment. Prospective, compartment-resolved biomarker studies are needed to match agonists, delivery systems, combination regimens, or inhibitory approaches to the appropriate tumor state.
SN - 1664-3224
ER -