Genomic landscape and tumor immune microenvironment of osteosarcoma: Bridging mechanistic insights to precision therapeutics.

Abstract

Osteosarcoma (OTS) is a highly aggressive primary bone malignancy characterized by profound genomic instability and a complex, immunosuppressive tumor immune microenvironment (TIME). Despite the established standard of neoadjuvant chemotherapy and surgical resection, the 5-year overall survival rates for metastatic or relapsed disease have remained stagnant at approximately 40% for decades. The high degree of heterogeneity and the "immune cold" nature of OTS pose significant challenges to the efficacy of conventional and emerging therapies. This review aims to summarize recent advances in the genomic and immunological landscape of OTS to inform personalized precision medicine. Genomic profiling reveals that OTS is driven by large-scale structural variations rather than single oncogenic drivers, with chromothripsis occurring in over 70% of cases. Frequent alterations in tumor suppressor genes, such as <i>TP53</i> (80%) and <i>RB1</i> (40%), fuel clonal evolution and therapeutic resistance. Furthermore, epigenetic dysregulation, including aberrant DNA methylation and alternative mRNA splicing, further complicates the molecular landscape. The OTS TIME is predominantly "cold," characterized by low T-cell infiltration and an abundance of M2-polarized tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown limited clinical success, emerging precision strategies, such as antibody-drug conjugates (ADCs) targeting B7-H3 or LRRC15, CAR-T cell therapies, and targeting of the CD47-SIRPα axis, demonstrate promising potential in preclinical and early-phase clinical trials. The transition from universal treatment to precision therapy in OTS requires a multi-omics approach for patient stratification. Future strategies must focus on overcoming the physical and immunological barriers of the TIME, reprogramming immunosuppressive cells, and exploiting novel targets like B7-H3 and MTAP deletion to improve outcomes for patients with advanced disease.