Gastric cancer (GC), as one of the deadliest gastrointestinal malignant tumors worldwide, poses a serious threat to the lives and health of patients. The incidence and mortality rates of GC rank fifth among all malignant tumors, according to the Data Communicator [1], [2]. In China, the number of new cases and deaths of gastric cancer in 2022 reached 358,700 and 260,400, respectively, accounting for 7.44% and 10.11% of all cancers [3].The five-year survival rate of patients with GC, especially those with local or distant metastases, is not optimistic, and is generally less than 10% [4]. The traditional treatment of gastric cancer has poor specificity and short disease control time, so the prognosis of patients is poor [5]. Recurrence and metastasis of gastric cancer are also major causes of poor prognosis [6]. Screening, development of early detection tools and translation of therapeutic tools in molecular biology are the current challenges and accomplishing these will greatly improve the prognosis and quality of survival of gastric cancer patients.

Tumor microenvironment (TME) is a general term for all non-tumor components, metabolites and secretions in tumor tissues. It has been found that TME has an important regulatory role in malignant phenotypes such as tumor growth, metastasis, and drug resistance [7]. Tumor-associated macrophages (TAMs) are an important component of TME and are closely related to the poor prognosis of many cancers. Activated macrophages are usually classified into two types, M1-type and M2-type [8], in which TAMs tend to exhibit an M2-type to promote the growth and metastasis of solid tumors [9]. In gastric cancer, M2 TAMs exert pro-angiogenic and immunosuppressive adverse effects [10], and TME gradually evolves into a state of sustained immune tolerance under long-term chronic inflammatory stimulation, which contributes to malignant progression of tumors and treatment resistance [11]. Therefore, targeting M2 TAM may provide a potential approach for therapeutic intervention in GC metastasis.

Post-translational modifications of proteins as important regulatory systems in eukaryotic cells are involved in physiological processes such as cell proliferation, cycle progression as well as disease progression. Methylation and ubiquitination modifications are important types of modifications in epigenetic regulation and are popular choices of therapeutic targets for clinical translation today. Imbalances in epigenetic modifications can affect GC progression by regulating methylation modifications and nucleosome remodeling, influencing the recruitment of transcription factors to chromosomes and thus the transcription of genes [12], [13]. Therefore, methylation modification is also an effective strategy for GC-targeted therapy. AlkB Homolog 1 (ALKBH1), a member of the AlkB family, is a nucleic acid demethylation catalytic enzyme, which is mainly involved in the demethylation of DNA and tRNA [14]. ALKBH1 also functions as an oncogene in various cancers by regulating demethylation in RNAs. For example, ALKBH1 is revealed to promote lung cancer invasion and migration by modulating 6-methyladenine (m6A) levels in RNA [15]. ALKBH1 is demonstrated to upregulate DDX18 via decreasing DNA 6 mA level and modulating its promoter activity, promoting the proliferation of head and neck squamous cell carcinoma cells [16]. It is also reported to impair the NRF1/AMPK signaling via DNA N6-methyladenine (6 mA) modification, promoting metabolic shift toward the Warburg effect that supports GC progression [17]. However, studies related to the regulation of TME by ALKBH1 are relatively rare, and Chang et al. have revealed for the first time that ALKBH1 is closely related to TAM [18], while how ALKBH1 regulates TAM and how it affects GC progression is currently unknown.

MYC is known as a transcription factor commonly activated via multiple genetic, epistatic, epigenetic and post-translational mechanisms in human malignancies [19]. In gastric cancer, for example, MYC is mediated by HECTD3 via polyubiquitination, promoting proliferation of gastric cancer cells [20]. SNHG26 binds to NCL to facilitate MYC translation, stimulating the proliferation and migration of GC cells [21]. LIN28B stabilizes c-MYC mRNA via m6A modification, supporting the proliferation, migration and glycolysis of GC cells [22]. Additionally, MYC also plays critical roles in mediating the crosstalk between cancer cells and TME as the cancer cell biology as well as the biological processes in TME such as invasion, migration, angiogenesis, and recruitment of tumor-infiltrating cells are regulated by MYC [23]. Emerging evidence has shown that MYC directly regulates genes related to macrophage polarization [24]. Moreover, correlation analysis has shown that expression of ALKBH1 and MYC was positively correlated in TCGA_STAD samples. Whether MYC functions as a downstream target of ALKBH1 in GC requires further investigation.

Ubiquitin specific peptidase 28 (USP28) is a deubiquitinase that is critically involved in the progression of various cancers [[25], [26], [27]]. Evidence has shown that USP28 can inhibit FBW7-mediated ubiquitination and increase the stability of MYC in cancer cells [[28], [29]]. In GC, USP28 is revealed to act as an oncogene that facilitates cell proliferation, migration, or stemness by modulating the ubiquitination-mediated proteasome pathway [[29], [30]]. Thus, the USP28/MYC axis is a promising target for anti-tumor therapy in GC. Additionally, bioinformatics analysis indicates the positive correlation between the expression of USP28 and ALKBH1 in GC, while the potential regulation between ALKBH1 and USP28 remains unclear.

The present study reveals for the first time the regulatory mechanism of ALKBH1 on TAMs, revealing the regulatory role of the emerging therapeutic target ALKBH1 from a novel perspective and enhancing the possibility of its clinical translation.