THBS1+ macrophages drive an immunosuppressive tumor microenvironment and promote progression in early-onset gastric cancer

Early-onset gastric cancer (EOGC) is characterized by aggressive clinical behavior and poor prognosis; however, the immunological features underlying its progression remain incompletely understood. Here, we performed single-cell RNA sequencing on EOGC tumors, matched adjacent mucosa, and traditional gastric cancer (TGC) samples, integrating these data with publicly available gastric cancer datasets to comprehensively characterize the EOGC tumor microenvironment. Our analyses revealed that EOGC exhibits an immunosuppressive “cold” microenvironment characterized by increased exhausted CD4+ T cells, impaired anti-tumor effector T-cell activity, and enhanced B-cell isotype switching from IgG to IgA, suggesting immune evasion. Notably, we identified a THBS1-expressing macrophage subset with prominent M2-like polarization that was associated with tumor progression and unfavorable prognosis. Functional experiments demonstrated that THBS1-overexpressing THP-1-derived macrophages promoted M2 polarization and enhanced malignant phenotypes in gastric cancer cell lines, whereas inhibition of THBS1 suppressed tumor growth in vivo. Together, these findings delineate a distinct immunosuppressive ecosystem in EOGC and provide insight into the potential role of THBS1+ macrophages in EOGC progression.