Biomarker-guided immunotherapy in osteosarcoma: from immune microenvironment profiling to patient stratification and combination strategies

Osteosarcoma remains a therapeutically difficult malignancy, particularly after metastatic relapse, and immune checkpoint blockade or adoptive cell therapy has not reproduced the durable responses achieved in more immunogenic cancers. The central translational problem is not a complete absence of immune activity, but marked interpatient, intratumoral, and spatial heterogeneity in immune access, antigen presentation, myeloid suppression, stromal exclusion, and target-antigen expression. This Mini Review synthesizes recent single-cell and spatial profiling studies with tissue, circulating, and clinical biomarker evidence to define a practical framework for biomarker-guided immunotherapy. Osteosarcoma ecosystems can contain lymphoid-excluded, myeloid-dominant, angiogenic-hypoxic, checkpoint-rich, and antigen-high states that may coexist within the same patient. Consequently, programmed death-ligand 1 (PD-L1) alone is unlikely to function as a reliable treatment-selection marker. A composite assessment integrating human leukocyte antigen (HLA) class I and antigen-processing competence, CD8/regulatory T-cell topology, macrophage and myeloid-derived suppressor cell programs, vascular and extracellular-matrix barriers, and quantitative surface-antigen density is more biologically defensible. Dynamic measurements, including circulating tumor DNA, soluble B7-H3, exosomal immune signals, and serial imaging, may complement tissue profiling but remain investigational. Clinical experience with checkpoint inhibitors, antiangiogenic combinations, mifamurtide, HER2-directed approaches, and emerging B7-H3-, GD2-, ALPL-1-, CD166-, IL-11Ralpha-, and NKG2D-based cellular therapies underscores the need to match mechanism to phenotype. Prospective studies should therefore use standardized, spatially resolved, and longitudinal biomarker panels to enrich trials, distinguish prognostic from predictive effects, and adapt therapy when immune exclusion or antigen escape emerges.