Immune exclusion as a recurrent immune-escape state driving treatment resistance in osteosarcoma: insights from single-cell, spatial, and multi-omics studies

Osteosarcoma remains a therapeutically challenging malignancy with durable responses limited by frequent treatment resistance. Although immune activity is detectable in many tumors, immunotherapy and combination strategies show limited clinical benefit, indicating immune dysfunction extends beyond tumor-intrinsic mechanisms. Growing evidence identifies immune exclusion as a key immunological barrier in osteosarcoma, characterized by spatial and functional segregation of immune cells from malignant areas despite their presence in the tumor microenvironment. Here, we use immune exclusion as a working term to describe contexts in which immune cells are present but have limited effective access to, or engagement with, malignant cells—distinct from immune desert (near-absence of infiltrates) and immune-cold states (weak effector activation despite some infiltration). In this mini-review, we focus on immune exclusion as a context-dependent immunological driver of treatment resistance in osteosarcoma. We integrate insights from single-cell sequencing, spatial profiling, and multi-omics studies to characterize the immunological features of immune exclusion, highlight bone-associated structural and regulatory factors, and explore how exclusion creates selective pressure leading to therapeutic failure. Emerging data indicate that immune exclusion represents a coordinated program involving tumor, stromal, and immune elements, resulting in impaired immune–tumor interaction and ineffective clearance. We discuss the translational implications, stressing immune-context modulation as essential for re-sensitization and noting that many current single-cell and spatial datasets remain limited in sample size, sampling sites, and treatment background. Framing resistance through immune exclusion offers an immune-centric framework for understanding and overcoming treatment resistance in osteosarcoma.