Navigating the immunosuppressive abyss: current hurdles and innovative breakthroughs in neoadjuvant immunotherapy for osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor of children and adolescents. Multiagent neoadjuvant chemotherapy once improved survival substantially, but outcomes have since plateaued. Delivering immunotherapy before surgery is attractive because the primary tumor, the tumor immune microenvironment (TIME), and the tumor-draining lymph nodes (TDLNs) remain intact. This setting may allow the TIME to be reconfigured while antigen sampling and T-cell priming are still possible. It does not, however, make the tumor a vaccine, nor does it imply that expanded tumor-infiltrating lymphocytes are tumor specific. Any benefit is instead likely to depend on antigen quality, human leukocyte antigen (HLA)-mediated presentation, the availability of tumor-reactive T-cell clones, and the reversibility of local immunosuppression. Translation remains constrained by a low but heterogeneous mutational burden, a myeloid-dominated microenvironment, and the absence of validated selection biomarkers. Preoperative treatment must also preserve its established non-immunological goals, namely downstaging to enable limb salvage and control of micrometastatic disease. We therefore examine the biological rationale, the current evidence, and the surgical, radiological, and pathological barriers to translation. We additionally consider how structural genomic instability constrains antigen availability and presentation, and how natural killer cell-directed strategies may inform barrier-matched design. On this basis we propose a barrier-matched development framework in which pathological response, spatial multi-omics, and molecular clearance jointly define success.