The multiple faces of cGAS-STING in antitumor immunity: prospects and challenges.

As a key sensor of double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) detects cytosolic dsDNA and initiates the synthesis of 2'3' cyclic GMP-AMP (cGAMP) that activates the stimulator of interferon genes (STING). This finally promotes the production of type I interferons (IFN-I) that is crucial for bridging innate and adaptive immunity. Recent evidence show that several antitumor therapies, including radiotherapy (RT), chemotherapy, targeted therapies and immunotherapies, activate the cGAS-STING pathway to provoke the antitumor immunity. In the last decade, the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry. However, up to now, none of STING agonists have been approved for clinical use. Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node (dLN), research on the optimal way to activate STING in tumor microenvironment (TME) appears to be a promising direction. Moreover, besides enhancing IFN-I signaling, the cGAS-STING pathway also plays roles in senescence, autophagy, apoptosis, mitotic arrest, and DNA repair, contributing to tumor development and metastasis. In this review, we summarize the recent advances on cGAS-STING pathway's response to antitumor therapies and the strategies involving this pathway for tumor treatment.

Efficacy of microwave ablation in the treatment of large benign thyroid nodules: a multi-center study.

OBJECTIVE: To evaluate the efficacy, safety, and improvement of symptoms by ultrasound-guided microwave ablation (MWA) for patients with large benign thyroid nodules (BTNs). METHODS: Eighty-seven patients with 87 BTNs (≥ 4 cm) treated with MWA between April 2015 and March 2021 were enrolled in this retrospective multicenter study, with clinical and ultrasound examinations performed at the 1st, 3rd, 6th, and 12th months. A multivariable linear mixed effects model was employed to explore the alterations in volume and volume reduction ratio (VRR), as well as the potential factors associated with VRR. RESULTS: The mean age of the 87 patients was 45.69 ± 14.21 years (range 18-76 years), and the ratio of men to women was 1:4.8. The mean volumes were much decreased at the 12th month after ablation compared to the initial volumes (p < .001). The mean VRR was 76.09% at the 12th month. The technique efficacy (VRR > 50%) was 90.80% at the 12th month. A multivariate analysis revealed that VRR was related to the initial volume (p = .015), annular flow (p = .010), and nodule composition (p = .024). The mean symptomatic score decreased from 4.40 ± 0.28 to 0.26 ± 0.06 at the 12th month (p < .001). At the same time, the mean cosmetic score decreased from 3.22 ± 0.10 to 1.31 ± 0.08 (p < .001). CONCLUSION: MWA could serve as a safe and effective therapy for large BTNs, significantly reducing the volume of BTNs and significantly improving compressive symptoms and appearance problems. CLINICAL RELEVANCE STATEMENT: Microwave ablation could serve as a safe and effective therapy for large benign thyroid nodules, leading to significant volume reduction and satisfied symptom and cosmetic alleviation period. KEY POINTS: • This multicenter study investigated the feasibility and safety of microwave ablation for large benign thyroid nodules. • After ablation, the nodule volume was significantly reduced, and patients' symptoms and appearance problems were significantly improved. • Microwave ablation is feasible for large benign thyroid nodules and has been a supplement treatment.

T-Lymphocyte Gene-Regulated CCL5 and Its Association with Extrahepatic Metastasis in Hepatocellular Carcinoma.

Background: Extrahepatic metastasis in hepatocellular carcinoma (HCC) greatly limits the prognostic survival of HCC patients. Levels of preoperative peripheral lymphocyte subsets and cytokines in the serum for predicting extrahepatic spread of hepatocellular carcinoma are still not common in clinical practice. The aim of this study is to investigate the value and mechanisms of peripheral lymphocyte subsets and cytokines in predicting extrahepatic spread of HCC. Methods: We used a retrospective design to analyze data pertaining to a total of 380 patients with HCC who were examined for peripheral T-lymphocyte subsets before receiving microwave ablation. We performed Cox regression analysis to screen out independent risk factors and used pathology specimens from the patients and public databases of liver cancer to investigate the correlation between cytokines and intra-tumor immune cells. Results: The CD4low group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD4high group (80% vs 69%, 67% vs 51%, and 57% vs 39%, respectively; HR 1.7 (1.2, 2.3), P = 0.0019). Similarly, the CD8high group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD8low group (65% vs 78%, 46% vs 64%, and 34% vs 54%, respectively; HR 0.6 (0.4, 0.8), P < 0.001). Patients with the CD4high/CD8low phenotype had significantly worse metastasis-free survival times compared to other patients (HR 2.0 (1.5, 2.8), P < 0.001). Additionally, T lymphocyte-specific genes (CD4, CD8) were correlated with CCL5 expression, which was also positively correlated with the level of intra-tumoral infiltrating CD8 T cells and the prognosis of HCC patients. Conclusion: Both CD4+ and CD8+ T lymphocyte subsets were independent risk factors for extrahepatic metastasis in HCC. Serum CCL5 levels could indicate the infiltration level of intra-tumoral CD8+ T cells and the risk of extrahepatic metastasis in HCC patients, aiding in patient risk stratification for metastasis.

Peripheral immune factors aiding clinical parameter for better early recurrence prediction of hepatocellular carcinoma after thermal ablation.

OBJECTIVES: Current predictors are largely unsatisfied for early recurrence (ER) of hepatocellular carcinoma (HCC) after thermal ablation. We aimed to explore the prognostic value of peripheral immune factors (PIFs) for better ER prediction of HCC after thermal ablation. METHODS: Patients who received peripheral blood mononuclear cells (PBMCs) tests before thermal ablation were included. Clinical parameters and 18 PIFs were selected to construct ModelClin, ModelPIFs and the hybrid ModelPIFs-Clin. Model performances were evaluated using area under the curve (AUC), and recurrence-free survival (RFS) were analyzed by Kaplan-Meier analysis and log-rank tests. RESULTS: 244 patients were included and were randomly divided in 3:1 ratio to discovery and validation cohorts. Clinical parameters including tumor size and AFP, and PIFs including neutrophils, platelets, CD3+CD16+CD56+ NKT and CD8+CD28- T lymphocytes were selected. The ModelPIFs-Clin showed increase in predictive performance compared with ModelClin, with the AUC improved from 0.664 (95%CI:0.588-0.740) to 0.801 (95%CI:0.734-0.867) in discovery cohort (p < 0.0001), and from 0.645 (95%CI:0.510-0.781) to 0.737(95%CI:0.608-0.865) in validation cohort (p = 0.1006). ModelPIFs-Clin enabled ER risk stratification of patients. Patients predicted in ModelPIFs-Clin high-risk subgroup had a poor RFS compared with those predicted as ModelPIFs-Clin low-risk subgroup, with the median RFS was 18.00 month versus 100.78 month in discovery cohort (p < 0.0001); and 24.00 month versus 60.35 month in validation cohort (p = 0.288). Patients in different risk subgroups exhibited distinct peripheral immune contexture. CONCLUSIONS: Peripheral immune cells aiding clinical parameters boosted the prediction ability for ER of HCC after thermal ablation, which be helpful for pre-ablation ER risk stratification.

Contrast-enhanced ultrasound features predict the prognosis of percutaneous microwave ablation of intrahepatic cholangiocarcinoma.

OBJECTIVE: To evaluate the prognostic effect of pre-operative contrast-enhanced ultrasound (CEUS) features on intrahepatic cholangiocarcinoma (ICC) after percutaneous microwave ablation (MWA). METHODS: A total of ICC 29 patients (average age 56.34 ± 9.78 years old, 33~75 years old) underwent MWA from March 2012 to December 2020, with a total of 58 lesions (0.5-8.1 cm, mean diameter, 2.68 ± 1.59 cm), and their pre-operative CEUS images and clinical data were collected and reviewed. Survival rate, local progression rate, intra- and extrahepatic metastasis rate were evaluated. Uni- and multivariate analysis were used to analyze the prognostic factors affecting the survival of ICC patients with pre-operative CEUS features. RESULTS: The median follow-up time after MWA was 18.43 months (4.17-93.13 months). 1-, 2-, and 3-year OS rates were 64.4%, 48.1% and 48.1%; 6-, 12-, 18-, 24-, 36-, 48-, and 60-month local progress and extrahepatic metastasis rates were 0.0%, 4.0%, 17.7%, 17.7%, 17.7%, 17.7%, 17.7% and 3.4%, 21.5%, 32.7%, 45.6%, 55.2%, 55.2% and 77.6%, respectively. Uni- and multivariate analysis showed that post-operative extrahepatic metastasis was an important factor for long-term survival of ICC patients after MWA (p = 0.006, 0.01), and Rim-enhancement feature of pre-operative CEUS was identified as an independent predictor of post-operative extrahepatic metastasis and long-term survival (p = 0.02, 0.02). CONCLUSION: Rim-enhancement feature of pre-operative CEUS is a predictor high post-operative extrahepatic metastasis and poor prognosis through distant microvascular metastasis after MWA of ICC patients. ADVANCES IN KNOWLEDGE: This study determined the important CEUS features of ICC and analyzed their impact on the prognosis of ICC patients after MWA, providing scientific guidance for better clinical treatment in the future.