The ALKBH1/MYC positive feedback loop regulates TAM polarization and remodels the tumor microenvironment to promote gastric cancer development.

The aim of this study was to investigate the mechanism of action of ALKBH1 in gastric cancer (GC) in regulating tumor-associated macrophage (TAM) polarization and remodeling tumor microenvironment (TME). Through bioinformatics analysis, cellular experiments, molecular biology techniques and in vivo HSC-NPG mouse model experiments, we systematically investigated the expression pattern of ALKBH1 in macrophages and its downstream signaling pathway. Our results showed that ALKBH1 was highly expressed in GC tissues and M2 macrophages, and was closely related to the degree of polarization of M2-type macrophages. Knockdown of ALKBH1 inhibited the polarization of M2 macrophages and strengthened the activity of M1-type macrophages, while enhancing anti-tumor immunity such as CD4+, CD8+ T cells, and NK cells. Further studies showed that ALKBH1 attenuated the m6A modification of USP28 mRNA, and up-regulated USP28 expression. USP28 increased deubiquitination of MYC thereby enhancing the stability of MYC protein, forming an ALKBH1/USP28/MYC positive feedback loop, which promotes M2 polarization and GC development. Knockdown of ALKBH1 rescued the above phenomena and inhibited tumor growth and metastasis in HSC-NPG mice. Our results indicated that ALKBH1 is a key factor regulating TAM polarization and remodeling TME in gastric cancer. Knockdown of ALKBH1 can inhibit gastric cancer progression by suppressing the polarization of M2-type macrophages and enhancing the anti-tumor immune response, which provides an important reference for the development of new therapeutic strategies for GC.