The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

Objectives. Given that microorganisms can become resistant to certain groups of drugs and considering also their ability to form biofilms, the development of new drugs that are active against adapted microflora is required. This study focused on the development of a new method for the synthesis of a promising compound, the branched hydrosuccinate oligohexamethylene guanidine (OHMGsucc), with high purity that meets the standards of the 14th edition State Pharmacopeia of the Russian Federation (SPRF). Previously proposed methods have managed to isolate this product, which, however, complies with the requirements of the outdated SPRF. Therefore, the main aim of this study was to update the regulatory framework for the indicated OHMG salt for its further use in the pharmaceutical industry according to modern standards.Methods. To control the residual impurities of hexamethylenediamine (HMDA) and guanidine hydrochloride (GHC), high-performance liquid chromatography (HPLC) was applied using a Thermo Scientific Dionex UltiMate 3000 chromatograph, and the chromatographic signals of the test solution with those of a standard sample solution obtained by a previously published conventional method were compared.Results. The HPLC experimental data indicated a significant difference in the quantitative content of HMDA and GHC observed for the new and older preparation method of the branched OHMGsucc, suggesting that the method disclosed in this article can be used to obtain highly pure OHMGsucc.Conclusions. The specified compound was standardized with the parameter “related impurities” according to the current (14th) edition of the SPRF. The effectiveness and reproducibility of the proposed method was experimentally confirmed. In addition, a process diagram for the preparation of the indicated OHMG salt was prepared.

The evolutionary conserved STING-cGAS pathway represents one of the most important cytosolic DNA sensing systems that is activated in response to viral invasion and/or damaged integrity of the nuclear envelope. The key outcome of this pathway is the production of IFN, which subsequently stimulates hundreds of genes. In oncology, the situation is a complex one since this pathway may serve either anti- or pro-oncogenic roles in a context-dependent fashion. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as from ruptured micronuclei, it results in the production of interferon which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression. In these cells, the pathway initiates a non-canonical nuclear factor κB transcriptional response, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in conjunction with cancer progression and development of new treatment modalities.

Objective: We evaluate the immunotherapeutic potential of the yellow fever virus vaccine strain 17D (YFV 17D) for intratumoral therapy of pancreatic cancer in mice. Methods: The cytopathic effect of YFV 17D on mouse syngeneic pancreatic cancers cells were studied both in vitro and in vivo and on human pancreatic cancers cells in vitro. Results: YFV 17D demonstrated a strong cytopathic effect against human cancer cells in vitro. Although YFV 17D did not exhibit a lytic effect against Pan02 mouse cells in vitro, a single intratumoral administration of 17D caused a delay in tumor growth and an increase in median survival by 30%. Multiple injections of 17D did not further improve the effect on tumor growth; however, it notably extended the median survival. Furthermore, preliminary immunization with 17D enhanced its oncotherapeutic effect. Conclusions: Intratumoral administration of yellow fever virus vaccine strain 17D delayed tumor in a murine model of pancreatic cancer. The fact that YFV 17D in vitro affected human cancer cells much more strongly than mouse cancer cells appears promising. Hence, we anticipate that the in vivo efficacy of YFV-17D-based oncolytic therapy will also be higher against human pancreatic carcinomas compared to its effect on the mouse pancreatic tumor.

Oncolytic viruses represent a promising class of immunotherapeutic agents for the treatment of malignant tumors. The proposed mechanism of action of various oncolytic viruses has initially been explained by the ability of such viruses to selectively lyse tumor cells without damaging healthy ones. Recently, there have emerged more studies determining the effect of the antiviral immunostimulating mechanisms on the effectiveness of treatment in cancer patients. Stimulation of innate immune cells by an oncolytic virus can initiate an adaptive antitumor immune response, yet at the same time, the antiviral mechanisms of the immune system can limit the spread of the virus, thereby reducing its effectiveness. Thus, the success of the clinical application of the oncolytic viruses directly depends on the three key components: tumor immunosuppression, antiviral responses, and antitumor immune responses. The review presents current data on the influence of pattern recognition receptors on the effectiveness of oncolytic viruses.

Introduction. Flaviviruses, possessing natural neurotropicity could be used in glioblastoma therapy using attenuated strains or as a delivery system for antitumor agents in an inactivated form. Objective. To investigate the sensitivity of glioblastoma and pancreatic carcinoma cell lines to vaccine strains of yellow fever and tick-borne encephalitis viruses. Materials and methods. Cell lines: glioblastoma GL-6, T98G, LN-229, pancreatic carcinoma MIA RaCa-2 and human pancreatic ductal carcinoma PANC-1. Viral strains: 17D yellow fever virus (YF), Sofjin tick-borne encephalitis virus (TBEV). Virus concentration were determined by plaque assay and quantitative PCR. Determination of cell sensitivity to viruses by MTT assay. Results. 17D YF was effective only against pancreatic carcinoma tumor cells MIA Paca-2 and had a limited effect against PANC-1. In glioblastoma cell lines (LN229, GL6, T98G), virus had no oncolytic effect and the viral RNA concentration fell in the culture medium. Sofjin TBEV showed CPE50 against MIA Paca-2 and a very limited cytotoxic effect against PANC-1. However, it had no oncolytic effect against glioblastoma cell lines (LN229, T98G and GL6), although virus reproduction continued in these cultures. For the GL6 glioblastoma cell line, the viral RNA concentration at the level with the infection dose was determined within 13 days, despite medium replacement, while in the case of the LN229 cell line, the virus concentration increased from 1 × 109 to 1 × 1010 copies/ml. Conclusion. Tumor behavior in organism is more complex and is determined by different microenvironmental factors and immune status. In the future, it is advisable to continue studying the antitumor oncolytic and immunomodulatory effects of viral strains 17D YF and Sofjin TBEV using in vivo models.