Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.

Introduction N6‐methyladenosine (m6A) is the most prevalent modification that occurs in messenger RNA (mRNA), affecting mRNA splicing, translation, and stability. This modification is reversible, and its related biological functions are mediated by “writers,” “erasers,” and “readers.” The field of viral epitranscriptomics and the role of m6A modification in virus–host interaction have attracted much attention recently. When Epstein–Barr virus (EBV) infects a human B lymphocyte, it goes through three phases: the pre‐latent phase, latent phase, and lytic phase. Little is known about the viral and cellular m6A epitranscriptomes in EBV infection, especially in the pre‐latent phase during de novo infection. Methods Methylated RNA immunoprecipitation sequencing (MeRIP‐seq) and MeRIP‐RT‐qPCR were used to determine the m6A‐modified transcripts during de novo EBV infection. RIP assay was used to confirm the binding of EBNA2 and m6A readers. Quantitative reverse‐transcription polymerase chain reaction (RT‐qPCR) and Western blot analysis were performed to test the effect of m6A on the host and viral gene expression. Results Here, we provided mechanistic insights by examining the viral and cellular m6A epitranscriptomes during de novo EBV infection, which is in the pre‐latent phase. EBV EBNA2 and BHRF1 were highly m6A‐modified upon EBV infection. Knockdown of METTL3 (a “writer”) decreased EBNA2 expression levels. The emergent m6A modifications induced by EBV infection preferentially distributed in 3ʹ untranslated regions of cellular transcripts, while the lost m6A modifications induced by EBV infection preferentially distributed in coding sequence regions of mRNAs. EBV infection could influence the host cellular m6A epitranscriptome. Conclusions These results reveal the critical role of m6A modification in the process of de novo EBV infection.

Edited by Qi-Qun TangEpstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo. Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RAS G12V ) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RAS G12V or chemotherapeutic drugs can induce senescence, and here we show that both RAS G12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.