Multiomics Analysis Reveals Immunosuppression In Oesophageal Squamous Cell Carcinoma Induced By Creatine Accumulation And Hk3 Deficiency Yingzhen Gao1 by Yingzhen Gao1†, Siyu He2†, Xiaoyan Meng1†, Kun Zheng2†, Heyang Cui3, 4†, Yikun Cheng3, Xinyuan Shen1, instant download after payment.

AbstractBackground Deep insights into the metabolic remodelling efects on the immune microenvironment of oesophageal squamous cell carcinoma (ESCC) are crucial for advancing precision immunotherapies and targeted therapies. This study aimed to provide novel insights into the molecular landscape of ESCC and identify clinically actionable targets associated with immunosuppression driven by metabolic changes.Methods We performed metabolomic and proteomic analyses combined with previous genomic and transcriptomic data, identifed multi-omics-linked molecular features, and constructed metabolic-immune interaction-based ESCC classifers in a discovery cohort and an independent validation cohort. We further verifed the molecular characteristics and related mechanisms of ESCC subtypes.Results Our integrated multi-omics analysis revealed dysregulated proteins and metabolic imbalances characterizing ESCC, with signifcant alterations in metabolites and proteins linked to genetic traits. Importantly, ESCC patients were stratifed into three subtypes (S1, S2, and S3) on the basis of integrated metabolomic and proteomic data. A robust subtype prediction model was developed and validated across two independent cohorts. Notably, patients classifed under the poorest prognosis subtype (S3 subtype) exhibited a signifcant immunosuppressive microenvironment. We identifed key metabolism-related biomarkers for the S3 subtype, specifcally creatine and hexokinase 3 (HK3). Creatine accumulation and HK3 protein defciency synergistically reprogrammed macrophage metabolism, driving M2-like