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Updated: Jul 19, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy
Mohammad Alshebremi1,2, Suzanne L Tomchuck3, Jay T Myers3
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Background:
Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood.
Methods:
The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9STINGwt or RMS 76-9STING-/-, along with other murine tumor models, in C57BL/6 or STING-/- (TMEM173 ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME).
Results:
The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components.
Conclusions:
Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches.
Insights
Cryoablation
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cryoablation shows promise for cancer treatment but has unpredictable clinical outcomes.
- The mechanisms behind cryoablation's immune effects and abscopal response are unclear.
Purpose of the Study:
- To investigate the mechanism by which cryoablation enhances therapeutic efficacy in metastatic tumor models.
- To explore the role of the STING (stimulator of interferon genes) signaling pathway in cryoablation's effectiveness.
Main Methods:
- Utilized mouse models of rhabdomyosarcoma (RMS) with varying STING pathway activity.
- Evaluated local tumor changes, metastasis, abscopal effects, and immune cell dynamics in the tumor microenvironment (TME).
Main Results:
- Cryoablation efficacy depends on both adaptive immunity and the STING signaling pathway.
- Tumor cell-intrinsic STING activation, not host STING, is crucial for local tumor control, reduced metastasis, and abscopal effects.
- STING pathway activation in tumor cells induces inflammatory responses in the TME, a mechanism also seen with STING agonist therapy.
Conclusions:
- The tumor cell-intrinsic STING pathway is essential for cryoablation's effectiveness.
- STING-related signaling component expression may predict therapy response.
- Further research is needed to fully understand STING-dependent pathways and inflammatory responses in cryoablation and related therapies.
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