Immunosuppression caused by incomplete radiofrequency ablation (iRFA) is a crucial factor affecting the effectiveness of RFA for solid tumors. However, little is known about the changes iRFA induces in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC), the primary application area for RFA. In this study, we found iRFA promotes a suppressive TIME in residual HCC tumors, characterized by M2 macrophage polarization, inhibited antigen presentation by dendritic cells (DCs), and reduced infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, the STING agonist MSA-2 was able to reorganize M2-like tumor-promoting macrophages into M1-like anti-tumor states and enhance antigen presentation by DCs. To optimize the therapeutic effect of MSA-2, we used a calcium ion (Ca2+) responsive sodium alginate (ALG) as a carrier, forming an injectable hydrogel named ALG@MSA-2. This hydrogel can change from liquid to gel, maintaining continuous drug release in situ. Our results suggested that ALG@MSA-2 effectively activated anti-tumor immunity, as manifested by increased M1-like macrophage polarization, enhanced antigen presentation by DCs, increased CTL infiltration, and inhibited residual tumor growth. ALG@MSA-2 also resulted in a complete regression of contralateral tumors and widespread liver metastases in vivo. In addition, the excellent biosafety of ALG@MSA-2 was also proved by blood biochemical analysis and body weight changes in mice. In summary, this study demonstrated that the immune cascade of ALG@MSA-2 mediated the STING pathway activation and promoted a favorable TIME which might provide novel insights for the RFA treatment of HCC. 

STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment.

Invading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality.

/pdf/unlocking-sting-as-a-therapeutic-antiviral-strategy-3dpvvs52.pdf

Unlocking STING as a Therapeutic Antiviral Strategy

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

Introduction Pseudorabies virus (PRV) is a herpesvirus that can infect domestic animals, such as pigs, cattle and sheep, and cause fever, itching (except pigs), and encephalomyelitis. In particular, the emergence of PRV variants in 2011 have resulted in serious economic losses to the Chinese pig industry. However, the signaling pathways mediated by PRV variants and their related mechanisms are not fully understood. Methods Here, we performed RNA-seq to compare the gene expression profiling between PRV virulent SD2017-infected PK15 cells and Bartha-K/61-infected PK15 cells. Results The results showed that 5,030 genes had significantly different expression levels, with 2,239 upregulated and 2,791 downregulated. GO enrichment analysis showed that SD2017 significantly up-regulated differentially expressed genes (DEGs) were mainly enriched in the binding of cell cycle, protein and chromatin, while down-regulated DEGs were mainly enriched in ribosomes. KEGG enrichment analysis revealed that the pathways most enriched for upregulated DEGs were pathways in cancer, cell cycle, microRNAs in cancer, mTOR signaling pathway and autophagy-animal. The most down-regulated pathways of DEGs enrichment were ribosome, oxidative phosphorylation, and thermogenesis. These KEGG pathways were involved in cell cycle, signal transduction, autophagy, and virus-host cell interactions. Discussion Our study provides a general overview of host cell responses to PRV virulent infection and lays a foundation for further study of the infection mechanism of PRV variant strain.

/pdf/comparative-transcriptomic-analysis-of-pk15-cells-infected-1b8cg94u.pdf

Comparative transcriptomic analysis of PK15 cells infected with a PRV variant and the Bartha-K/61 vaccine strain

Fish SCD1 promotes SGIV infection via modulating the formation of lipid droplets and TBK1/MDA5-activated IFN signal pathway

Pseudorabies (PR) is a domestic and wild animal infectious disease caused by the pseudorabies virus (PRV) and is one of the major infectious diseases that endanger the global swine industry. Studies have reported that PRV may achieve cross-species transmission from pigs to humans in recent years. Therefore, in-depth exploration of the relationship between PRV and host proteins is of great significance for elucidating the pathogenic mechanism of PRV and anti-PRV infection. Here, we report that heat shock protein 27 (HSP27) ubiquitinates and degrades cyclic GMP-AMP synthase (cGAS) and attenuates cGAS-mediated antiviral responses, thereby promoting PRV infection. Overexpression of HSP27 promoted PRV proliferation in vitro, while knockdown of HSP27 inhibited PRV infection. Importantly, we found that HSP27 inhibited PRV infection or poly(dA:dT)-activated IFN-β expression. Further studies found that HSP27 may inhibit cGAS-STING-mediated IFN-β expression through targeting cGAS. In addition, we found that HSP27 can suppress the expression of endogenous cGAS in different cells at both gene transcription and protein expression levels, and that HSP27 interacts with and ubiquitinates cGAS. In conclusion, we reveal for the first time that HSP27 is a novel negative regulator of the cGAS-STING signaling pathway induced by PRV infection or poly(dA:dT) activation and demonstrate that HSP27 plays a crucial role in PRV infection.

/pdf/hsp27-attenuates-cgas-mediated-ifn-b-signaling-through-1j7p1pbx.pdf

HSP27 Attenuates cGAS-Mediated IFN-β Signaling through Ubiquitination of cGAS and Promotes PRV Infection

Mammalian Reovirus Μ1 Protein Attenuates RIG-I and MDA5-Mediated Signaling Transduction by Blocking IRF3 Phosphorylation and Nuclear Translocation

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HSP27 Attenuates cGAS-Mediated IFN-β Signaling through Ubiquitination of cGAS and Promotes PRV Infection

Mammalian Reovirus Μ1 Protein Attenuates RIG-I and MDA5-Mediated Signaling Transduction by Blocking IRF3 Phosphorylation and Nuclear Translocation