YB-1 inhibition suppresses osteosarcoma growth and reverses tumor immunosuppression.

Osteosarcoma (OS), the most common primary bone malignancy in adolescents and young adults, is still marked by poor long-term survival and poor mortality. Although immune checkpoint blockade (ICB) has transformed treatment for several cancers, its benefit in OS has been minimal, largely due to OS'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 OS to ICB. Here, we evaluate SU056, a small-molecule YB-1 inhibitor, which both suppressed intrinsic OS tumor growth and remodeled the tumor microenvironment (TME). SU056 treatment markedly reduced immunosuppressive populations, including regulatory T cells (Tregs) and M2-polarized tumor-associated macrophages (TAMs), while enhancing infiltration of granzyme B-positive cytotoxic CD8⁺ T cell 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 OS.