YB-1 Inhibition Suppresses Osteosarcoma Growth and Reverses Tumor Immunosuppression

Abstract Osteosarcoma, the most common primary bone malignancy in adolescents and young adults, is still marked by poor long-term survival and high mortality. Although immune checkpoint blockade (ICB) has transformed treatment for several cancers, its benefit in osteosarcoma has been minimal, largely due to osteosarcoma’s “immune-cold” phenotype characterized by scarce tumor-infiltrating lymphocytes. Novel strategies are urgently needed to overcome this resistance. Y-box binding protein 1 (YB-1), a pro-oncogenic member of the cold-shock protein superfamily, represents a promising target to sensitize osteosarcoma to ICB. In this study, we evaluate SU056, a small-molecule YB-1 inhibitor, which both suppressed intrinsic osteosarcoma tumor growth and remodeled the tumor microenvironment. SU056 treatment markedly reduced immunosuppressive populations, including regulatory T cells and M2-polarized tumor-associated macrophages, while enhancing the infiltration of granzyme B-positive cytotoxic CD8+ T and NK cells. Combination therapy with SU056 and anti–PD-1 blockade produced superior tumor growth inhibition and significantly prolonged survival compared with either monotherapy. These findings highlight SU056 as a potent immunomodulatory agent and support its coadministration with ICB as a promising therapeutic approach for osteosarcoma.