GC is one of the most common malignant cancer and ranked as the fourth leading cause of cancer-related deaths all around the world [
1‐
4]. Advanced treatments have helped improving the prognosis of GC. The 5-year survival of GC patients at stage IA and IB treated with surgery are between 60 and 80%. However, the 5-year survival of advanced stage tumor remain poor [
5]. Thus, effective prognostic markers and potential therapeutic targets are needed to help clinicians select the most suitable therapy for GC patients.
KDMs are a family of enzymes that play a crucial role in the regulation of gene expression through the dynamic modification of histone proteins [
6]. These enzymes catalyze the removal of methyl groups from lysine residues on histones, which in turn modulates chromatin structure and subsequently influences transcriptional activity. Mutations or aberrant expression of
KDMs have been observed in various types of cancer, including leukemia, breast cancer, prostate cancer, lung cancer, and colorectal cancer, among others [
7]. Some
KDMs have been identified as oncogenes, promoting tumor growth and progression, while others have been found to act as tumor suppressors, preventing cancer development [
8]. These diverse roles depend on the specific
KDM, its target genes, and the cellular context [
9]. For example,
KDMs affect the methylation of
H3K4,
H3K9,
H3K27, and
H3K36, which can regulate the expression of tumor suppressor genes or oncogenes [
10,
11]. Emerging evidences indicate
KDMs are related to various cancers. In head and neck squamous cell carcinomas (HNSCC),
KDM1,
KDM4,
KDM5, and
KDM6 proteins are regarded as the useful therapeutic targets [
12]. However, few studies have comprehensively explored the role
KDM demethylase genes in clinical outcomes of gastric cancer patients. Considering that targeting KDMs has become an attractive therapeutic strategy in cancer treatment and several small molecule inhibitors targeting KDMs, particularly those in the JmjC family, have been developed and are undergoing preclinical and clinical evaluation, there is an urgent need for research investigating the prognostic role of KDM genes in GC [
13,
14]. This will facilitate the discovery of potential KDM-targeted therapies for the treatment of GC patients.
TME plays a crucial role in cancer development. Within the TME, factors such as CD8 + T cells and macrophages have been identified as important determinants of response to immunotherapy or chemotherapy [
15,
16]. Alterations in the abundance of TME cells, such as CD8 + T cells, macrophages, and fibroblasts, have been found to be associated with clinical outcomes in a variety of cancers, including gastric cancer [
17‐
19]. The correlation between TME cell infiltration and KDMs has seldom been reported in GC. This study aimed to integrate mRNA and genomic data for an in-depth analysis of KDMs, with the goal of uncovering the underlying relationship between KDM genes and GC tumorigenesis. The findings could offer novel insights into the application of various therapeutic treatments for GC patients, based on the regulation of histone demethylase KDMs.