ADA2high tumor cell-derived inosine induces an immunosuppressive microenvironment in gastric cancer by promoting macrophage M2 polarization

Abstract Metabolic alterations within the tumor microenvironment (TME) can reshape the polarization state of tumor-associated macrophages (TAMs) and weaken antitumor immunity, yet the underlying mechanisms remain unclear. In this study, we integrated multiple gastric cancer (GC) single-cell RNA sequencing (scRNA-seq) datasets and identified a tumor cell population with high adenosine deaminase 2 (ADA2) expression that is significantly associated with poor prognosis. Further investigations revealed that this tumor cell population induces M2 polarization of TAMs through the secretion of the metabolite inosine. Mechanistically, inosine derived from ADA2 high tumor cells promotes the synthesis of S-adenosylmethionine (SAM) in macrophages through two complementary pathways, upregulating MAT2A expression and serving as a carbon source. The resulting increase in SAM elevates global methylation levels and drives M2 polarization. Targeting the inosine-MAT2A-SAM axis markedly suppresses tumor growth. Taken together, this study reveals a previously unrecognized mechanism through which tumor cell-derived metabolites modulate the immune microenvironment, providing a potential therapeutic target and strategy for GC immunotherapy.