TMCC2 suppresses osteosarcoma growth and is associated with M1-like macrophage polarization

Abstract Osteosarcoma is an aggressive bone malignancy, but how TMCC2 affects tumor cell behavior and macrophage responses remains unclear. We analyzed public bulk and single-cell transcriptomic datasets and performed functional experiments. TMCC2 expression was lower in osteosarcoma samples than in non-tumoral bone samples. Higher expression was associated with longer overall survival in the TARGET-OS cohort. In the single-cell dataset, TMCC2 expression was relatively high in macrophages and monocytes. Overexpression of TMCC2 reduced cell viability, wound closure, and the number of cells crossing Transwell membranes and increased apoptosis in U2OS and HOS cells. Knockdown in HOS cells had the opposite effects. TMCC2-overexpressing U2OS cells also accumulated in the G1 phase. These effects were accompanied by changes in cellular TGF-β1 levels and SMAD2/3 phosphorylation. Conditioned medium from TMCC2-overexpressing osteosarcoma cells increased CD86 and iNOS expression and reduced migration in THP-1-derived macrophages that had already received an M1-like stimulus. In mice, TMCC2-overexpressing U2OS xenografts grew more slowly and showed more prominent CD68 and CD80 staining. These findings support a growth-suppressive role for TMCC2 in the models tested and suggest a link to macrophage responses. Whether macrophages mediate tumor suppression or secreted TGF-β1 drives the conditioned-medium effects remains to be established.