Cytokine epigenetics network for gastric cancer progression and chemoresistance.

Gastric cancer (GC) is a leading cause of cancer mortality due to late diagnosis, metastasis, and therapy resistance. Epigenetic modifications rewire the cytokine network, facilitating the development, progression, and chemoresistance of GC. Cytokines regulate immune and inflammatory responses through various pathways, including the IL-6/JAK/STAT pathway, MAP Kinase, NF-κB signaling, IL-8/NF-κB, and the TGF-β axis, which sustain persistent inflammation and oncogenic signaling. The expression of these regulatory molecules is tightly controlled by epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and miRNA sponging. In addition, this is influenced by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which impact the tumor microenvironment and tumor survival. H. pylori and EBV further remodel cytokine epigenetic networks, promoting tumor progression. LncRNA and circRNAs can play dual roles, acting as both oncogenic and tumor-suppressive agents, where oncogenic ncRNAs, via drug efflux, apoptosis inhibition, autophagy, PD-L1 stabilization, and CSC maintenance, whereas tumor-suppressive ncRNAs restore chemosensitivity and antitumor immunity by reactivating PTEN, MHC-I, and apoptosis, proving to be promising biomarkers and therapeutic targets. Various clinical trials are also discussed in this review.