Immune and stromal signaling networks in chordoma: an evidence-weighted review of ligand–receptor interactions and therapeutic implications

PURPOSE: This scoping review aimed to systematically map reported ligand-receptor (L-R) interactions in chordoma, classify the strength of supporting evidence, and integrate mechanistic, spatial, and clinical findings to inform translational prioritization. METHODS: A systematic search of PubMed, Embase, and Web of Science (2000-2024) identified original studies reporting L-R signaling in chordoma. Data on experimental models, signaling axes, functional assays, and clinical correlations were extracted using a predefined template. Evidence for each axis was graded as level A (causal/functional validation), level B (protein or spatial confirmation), or level C (inferred transcriptomic evidence). The review followed PRISMA-ScR and JBI scoping methodology. RESULTS: Thirty studies met inclusion criteria. Ten recurrent signaling circuits were identified. Receptor tyrosine kinase pathways-EGF → EGFR and PDGF → PDGFR-were the most consistently validated, supported by multi-modal experimental evidence and limited clinical activity. IL-6 → IL-6R → STAT3 emerged as a stromal-immune-tumor axis with level A functional validation, linking CAF and macrophage activation to tumor invasion. TGF-β → TGFβR signaling and the newly defined ER-stress CAF-derived IER2 → GMFG → ITGB1 axis were supported by single-cell/spatial profiling with early functional evidence. PD-1/PD-L1 expression showed consistent prognostic correlations but lacked mechanistic validation. CONCLUSION: This review provides the first evidence-weighted map of intercellular signaling in chordoma. While RTK autocrine loops remain the most established, emerging cytokine- and CAF-mediated pathways highlight new biological mechanisms and potential therapeutic targets. Bridging single-cell discovery with functional validation and clinical translation will be essential to advance microenvironment-directed therapies in chordoma.