A Circulating GPNMB-Based Multimodal Model Integrates Tumor-Immune Crosstalk to Predict Immunotherapy Response in Esophageal Cancer

Neoadjuvant immunotherapy improves outcomes in esophageal squamous cell carcinoma (ESCC), yet ~70% of patients fail to respond. Pretreatment biopsies and plasma provide critical opportunities for biomarker discovery. Here, we performed plasma proteomic profiling and identified soluble glycoprotein non-metastatic melanoma protein B (sGPNMB) as the most elevated circulating protein in non-responders. Mechanistically, tumor cell-derived sGPNMB suppressed CD8+ T cell receptor (TCR) signaling via the SDC4-CD148 axis to induce functional exhaustion, with secretion being required for its immunosuppressive activity. Cancer-associated fibroblast-epithelial (CAF-Epi) niches promoted SOX2 upregulation in tumor cells, transcriptionally activating GPNMB expression. In humanized PDX models, circulating GPNMB levels predicted response to PD-1 blockade, and GPNMB inhibition synergised with therapy. Across retrospective cohorts and a prospective clinical trial, a multimodal model combining plasma GPNMB levels, CAF-Epi niche detection, and clinical-pathological features achieved robust predictive accuracy for immunotherapy response and survival. These findings establish a spatial-circulating biomarker framework for precision ESCC immunotherapy.