Yan Zhang

The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway, as a key DNA sensor, plays a significant role in the regulation of innate immune responses. This pathway can be activated by sensing abnormal DNA, and is of great significance for resisting the invasion of pathogenic microorganisms and maintaining tissue homeostasis. In addition, the cGAS‐STING pathway plays a dual role in cancer, and oncogenic viruses can cause cell carcinogenesis in the body through multiple mechanisms, thereby affecting human health. This manuscript reviews the vital role of cGAS‐STING in the immune process, as well as the fact that viruses causing human tumor lesions can activate cGAS‐STING, leading to virus inhibition and further preventing the occurrence and development of related cancers, and the paradoxically promoted progression of related cancers by viruses through cGAS‐STING. And summarize the agonists and inhibitors that act in different ways based on the activation mechanism of cGAS‐STING.

Human oncoviruses infect host cells and drive tumorigenesis. Macrophages, as key innate immune cells, exhibit functional heterogeneity and polarization plasticity. They are broadly classified into proinflammatory M1 and anti-inflammatory M2 states, which determine their role in immunity and tissue homeostasis. We summarized the recent experimental and clinical studies on the interactions between macrophages and the major oncoviruses, including Epstein-Barr virus (EBV), Kaposi's Sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human papillomavirus (HPV). We focus on how viral proteins, non-coding RNAs, and extracellular vesicles reprogram macrophage functions and discuss emerging macrophage-targeted therapeutic strategies. Oncoviruses drive macrophages toward pro-tumor M2 or dysfunctional M1 states by altering cytokine secretion, activating signaling pathways, such as cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and nuclear factor kappa B (NF-κB), and reprogramming metabolic pathways. New therapeutic strategies targeting macrophages, including polarization modulation, bispecific antibodies, nanomedicine delivery systems, and immune checkpoint strategies, show promise in enhancing antiviral and antitumor immunity. Macrophages can sense various oncoviruses and play a role in oncovirus infection, chronic inflammation, and virus-driven tumorigenesis. Potential therapeutic strategies targeting macrophages offer new avenues for the precision treatment of oncovirus-associated diseases.

The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family, comprises highly conserved RNA-binding proteins that play crucial roles in post-transcriptional gene regulation. Recent evidence suggests that IGF2BP proteins contribute to the pathogenesis and progression of multiple cancers and also participate in the regulation of viral infections and virus-associated tumors. This review provides a systematic synthesis of the biological functions of the IGF2BP family and its regulatory roles in viral life cycles. Particular emphasis is placed on oncogenic viruses, including hepatitis B and C viruses, human papilloma virus, Epstein–Barr virus, and human immunodeficiency virus, which co-opt IGF2BP proteins to promote viral replication and support tumorigenic processes. These mechanisms include the stabilization of viral RNA, modulation of host metabolic pathways, and immune responses. Furthermore, this review evaluates the therapeutic potential of targeting IGF2BP proteins in virus-associated tumors, offering new insights and future directions for research in this area.

Significance: Reactive oxygen species (ROS) are a double-edged sword in the context of oncoviruses. The effects of ROS on cells depend on the cellular environment, the stage of the disease, and the specific molecular pathways involved. In general, ROS levels in oncovirus-infected cells are usually increased and produce two distinct outcomes on cancer progression and metastasis through multiple mechanisms. Therefore, identifying the relationship between ROS and tumor viruses at the molecular level is essential for cancer prevention and treatment. Recent Advances: ROS play an important role in oncoviral infection and disease progression. The excessive accumulation of ROS induces ferroptosis, which has an important role in tumor therapy and the immune microenvironment, thus providing a theoretical basis for the development of new anticancer treatment strategies. Critical Issues: This review summarizes the complex relationship between ROS and oncoviral infection, with the aim of providing a deeper understanding of tumor pathogenesis and new therapeutic strategies. Future Directions: The relationship between ROS induced by oncoviral infection and host metabolic pathways, including lipids, lipoproteins, amino acids, and polyamines. Understanding how metabolism is reprogrammed in cancer cells may elucidate the impact of these processes on viral infection and tumor progression and help develop effective treatment strategies. Antioxid. Redox Signal. 43, 528–546.

Aims: Epstein-Barr virus (EBV)-associated gastric cancer (GC) accounts for about 9% of GC patients, but its pathogenesis remains unclear. Glutathione peroxidase 4 (GPX4) is an important antioxidant enzyme that is highly expressed in various tumors and is associated with viral infections. This study aimed to clarify the relationship between EBV and GPX4 and the role of GPX4 in the occurrence and development of EBV-associated GC. Results: EBV infection leads to oxidative stress and excessive generation of reactive oxygen species (ROS) in GC cells. At the same time, EBV upregulates the expression of antioxidant enzyme GPX4 through the latent membrane protein 2A (LMP2A)/p62/Kelch-like ECH-associated protein 1(Keap1)/nuclear factor (erythroid-derived 2)-like 2 (NRF2) axis, eliminating excessive ROS to balance redox homeostasis and maintain its own survival. The high expression of GPX4 in GC inhibits EBV's immediate early lytic gene BZLF1 expression, thereby inhibiting EBV reactivation, and promotes cell migration and proliferation by upregulating lipocalin-2 (LCN2). Innovation: This study is the first to demonstrate that EBV-induced GPX4 expression via the LMP2A/p62/Keap1/NRF2 axis contributes to both viral latency and tumor progression in GC. Conclusion: EBV activates the p62/Keap1/NRF2 signaling pathway through LMP2A to upregulate the expression of GPX4, thereby alleviating oxidative stress caused by viral infection and maintaining the redox homeostasis in GC cells. Such enhanced expression not only maintains the latent infection of EBV but also promotes the malignant transformation of GC cells through LCN2. Antioxid. Redox Signal. 00, 000-000.

EBV infection is closely related to the occurrence and development of gastric cancer (GC). EphA2 is an important oncogenic protein in the progression of a variety of tumors. However, the relationship between EphA2 and EBV in EBV-associated GC (EBVaGC) remains unclear. Immunohistochemical and molecular experiments were performed to compare EphA2 expression between EBVaGC and EBV-negative gastric cancer (EBVnGC). The role of LMP2A in EphA2 expression was evaluated by transfection of LMP2A plasmid or siRNA. The S901 and Y772 phosphorylation site mutant plasmids of EphA2 were constructed to study their biological functions. EphA2 expression was significantly downregulated in EBVaGC tissues and cell lines. LMP2A down-regulates EphA2 expression through the PI3K/AKT signaling pathway and autophagy pathway. pS901-EphA2 and pY772-EphA2 promote the malignant function of GC cells. In addition, pS901-EphA2 promotes the lytic reactivation of EBV by activating the JNK signaling pathway. Our data suggests that pS901-EphA2 and pY772-EphA2 play a role in the malignant characteristics of GC, and that pS901-EphA2 induced phosphorylation of JNK is a potential mechanism by which EphA2 promotes the lytic reactivation of EBV. LMP2A is involved in EBVaGC progression and maintenance of EBV latent infection by down-regulating EphA2 expression.

Iron is crucial for cell survival and maintaining normal physiological functions. Viral infections can disrupt cellular iron metabolism, leading to inflammation and cancer. Ferritin, a key iron-binding protein, consists of ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL) and helps regulate systemic iron balance, both implicated in various tumor developments. Epstein-Barr virus (EBV), the first oncogenic virus discovered in humans, can induce the development of EBV-associated gastric cancer (EBVaGC). However, the regulatory mechanisms and functions of FTH1 and FTL in EBVaGC are poorly understood. This study aimed to investigate how EBV regulates FTH1 and FTL and their roles in the development of EBVaGC. We show that EBV is able to remodel intracellular iron metabolism, affecting the expression of FTH1 and FTL. EBV-encoded LMP2A promotes the expression of FTH1 and FTL by up-regulating p62 and blocking the autophagy degradation pathway, thus participating in the occurrence and development of EBVaGC. Knocking down FTL inhibits cell migration and proliferation, and promotes apoptosis, whereas FTH1 knockdown has negligible effects on these cellular functions. Additionally, we found that ferritin enhanced the inflammatory state of gastric cancer cells. Overall, our findings highlight the significant impact of EBV on ferritin, underscoring a previously unrecognized role of ferritin in the progression of EBVaGC. This novel pathway could offer new therapeutic targets for the treatment of EBVaGC.