Furthermore, as a secreted glycoprotein, the in vitro osteosarcoma cells and CD8+ T cells co-culture system demonstrated that STC2 hampered the antitumor effect of cytotoxic CD8+ T cell by reducing the expression of IFN-γ and Granzyme B. Collectively, we demonstrated that the ER stress related gene STC2 has the potential to modulate immune suppression by reducing MHC-I molecule expression in osteosarcoma cells and impairing CD8+ T cell function within the TME. Here, IFNG is linked to osteosarcoma.