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

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. 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. 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. 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.