Immune escape biomarkers in chondrosarcoma: implications for PD-1/PD-L1 blockade and precision combination therapy

Chondrosarcoma is a biologically heterogeneous bone malignancy for which surgery remains the principal curative treatment, while systemic options for unresectable or metastatic disease are limited. Immune checkpoint blockade has produced occasional durable responses, particularly in dedifferentiated chondrosarcoma, but clinical activity is inconsistent and validated treatment-selection biomarkers are lacking. This Mini Review synthesizes chondrosarcoma-specific evidence on PD-L1, CD8-positive tumor-infiltrating lymphocytes, HLA class I (HLA-I)/ β 2-microglobulin integrity, the CD68/CD8 ratio, CSF1R-positive tumor-associated macrophages (TAMs), granulocytic myeloid-derived suppressor cells (G-MDSCs), B7-H3, and immune-phenotype classification. These markers capture complementary immune-escape processes but are largely descriptive, prognostic, or mechanistic rather than prospectively validated predictors of checkpoint-inhibitor benefit. IDH1/2 mutations and D-2-hydroxyglutarate (D-2HG) provide an additional metabolic framework, although direct evidence connecting D-2HG with immune escape in chondrosarcoma remains incomplete. The multicenter, non-randomized phase 2 FLAIL-C study reported higher 6-month progression-free survival with anti-PD-1 plus anlotinib than with anlotinib alone, particularly in dedifferentiated disease; its non-randomized design limits causal interpretation. Future subtype-stratified trials should test composite, spatially informed panels and assess mutant-IDH inhibition, myeloid modulation, and B7-H3-directed cellular therapy, the last of which remains preclinical in chondrosarcoma.