BackgroundDeep insights into the metabolic remodelling effects 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.MethodsWe performed metabolomic and proteomic analyses combined with previous genomic and transcriptomic data, identified multi-omics-linked molecular features, and constructed metabolic-immune interaction-based ESCC classifiers in a discovery cohort and an independent validation cohort. We further verified the molecular characteristics and related mechanisms of ESCC subtypes.ResultsOur integrated multi-omics analysis revealed dysregulated proteins and metabolic imbalances characterizing ESCC, with significant alterations in metabolites and proteins linked to genetic traits. Importantly, ESCC patients were stratified 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 classified under the poorest prognosis subtype (S3 subtype) exhibited a significant immunosuppressive microenvironment. We identified key metabolism-related biomarkers for the S3 subtype, specifically creatine and hexokinase 3 (HK3). Creatine accumulation and HK3 protein deficiency synergistically reprogrammed macrophage metabolism, driving M2-like TAM polarization. This metabolic shift fostered an immunosuppressive microenvironment that accelerated tumour progression. These results highlight the potential of targeting creatine metabolism to improve the efficacy of immunotherapy and targeted therapy for ESCC.ConclusionsOur analysis reveals molecular variation in multi-omics linkages and identifies targets that reverse the immunosuppressive microenvironment through metabolic remodelling improving immunotherapy and targeted therapy for ESCC.
基金：
This work was supported by the following: Shenzhen Medical Research
Funds (No. C2303002 to Y.P.C. and X.L.C.), the National Natural Science
Foundation of China (No. U21A20372 and 82341024 to Y.P.C., No. 82172930
to W.M.Z., No. 82302916 to H.Y.C., No. 82394411 to L.Z.D., and No. 82103143
to N.D.); the National Key R&D Program of China (No. 2021YFC2501001 to
X.L.C.); the Science and Technology Innovation Team of Shanxi Province
(No. 202204051001024 to L.Z.); the Science and Technology Achievements
Transformation Project of Shanxi Province (No. 202204021301062 to L.Z.); the
Special Fund for Science and Technology Innovation Teams of Shanxi Province
(No. 201605D131045-16 to Y.P.C.); the West China Hospital 135 project (No.
ZYYC23013 to L.Z.D.); Shanxi Province Higher Education “Billion Project” Science
and Technology Guidance Project (No. BYJL005 to L.Z.); direct grant from
the Chinese University of Hong Kongand (No. 2024.147 to H.Y.C.); the Fundamental
Research Program of Shanxi Province (No. 202303021221236 to B.Y.).
第一作者机构：[1]Shanxi Med Univ, Inst Pathogenesis & Clin Translat Res Esophageal C, Sch Basic Med, Taiyuan 030001, Shanxi, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[1]Shanxi Med Univ, Inst Pathogenesis & Clin Translat Res Esophageal C, Sch Basic Med, Taiyuan 030001, Shanxi, Peoples R China[4]Shanxi Med Univ, Shanxi Bethune Hosp, Tongji Shanxi Hosp,Hosp 3, Shanxi Acad Med Sci,Canc Ctr, Taiyuan 030032, Shanxi, Peoples R China[9]Shanxi Med Univ, Hosp 2, Taiyuan 030001, Shanxi, Peoples R China[10]Shanxi Med Univ, Key Lab Cellular Physiol, Minist Educ, Taiyuan 030001, Shanxi, Peoples R China
推荐引用方式(GB/T 7714)：
Gao Yingzhen,He Siyu,Meng Xiaoyan,et al.Multi-omics analysis reveals immunosuppression in oesophageal squamous cell carcinoma induced by creatine accumulation and HK3 deficiency[J].GENOME MEDICINE.2025,17(1):doi:10.1186/s13073-025-01465-1.
APA：
Gao, Yingzhen,He, Siyu,Meng, Xiaoyan,Zheng, Kun,Cui, Heyang...&Zhang, Ling.(2025).Multi-omics analysis reveals immunosuppression in oesophageal squamous cell carcinoma induced by creatine accumulation and HK3 deficiency.GENOME MEDICINE,17,(1)
MLA：
Gao, Yingzhen,et al."Multi-omics analysis reveals immunosuppression in oesophageal squamous cell carcinoma induced by creatine accumulation and HK3 deficiency".GENOME MEDICINE 17..1(2025)
生物学