Inhibition of the PERK pathway could exacerbate ER stress and promote apoptosis in osteosarcoma cells, while also altering the polarization state of TAMs from the immunosuppressive M2 phenotype to the anti-tumorigenic M1 phenotype, thereby disrupting tumor immunosuppression. This study provides a new perspective on the biological mechanisms of osteosarcoma and opens up a new direction for its therapeutic strategies.