Abstract Neoadjuvant immunotherapy improves outcomes in esophageal squamous cell carcinoma (ESCC), yet ∼70% of patients fail to respond. Pretreatment biopsies and plasma thus 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 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, plasma 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 mechanistically grounded, spatial-circulating biomarker framework for precision immunotherapy in ESCC. Citation Format: Liang Zhu, Xiaoyuan Wang, Guoyu Cheng, Yancheng Lai, Lan Lan, Zhenghao Dong, Zhixuan You, Xinjie Chen, Ziyi He, Xinyi Xiao, Lingxuan Zhu, Rucheng Liu, Shaosen Zhang, Dongxin Lin, Chen Wu, Jiang Chang. A circulating GPNMB-based multimodal model integrates tumor-immune crosstalk to predict immunotherapy response in esophageal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7724.
Zhu et al. (Fri,) studied this question.