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Updated: Jun 28, 2026
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Multi-omics analysis reveals immunosuppression in oesophageal squamous cell carcinoma induced by creatine
Yingzhen Gao1, Siyu He2, Xiaoyan Meng1
1School of Basic Medicine, Institute for Pathogenesis and Clinical Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
Background:
Deep 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.
Methods:
We 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.
Results:
Our 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.
Conclusions:
Our 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.
Insights
Metabolic reprogramming in oesophageal squamous cell carcinoma (ESCC) creates an immunosuppressive tumor microenvironment. Targeting creatine metabolism and HK3 may reverse this, improving immunotherapy and targeted therapy efficacy for ESCC patients.
Area of Science:
- Oncology
- Immunology
- Metabolomics
Background:
- Metabolic alterations significantly impact the immune microenvironment in oesophageal squamous cell carcinoma (ESCC).
- Understanding these metabolic changes is vital for developing effective immunotherapies and targeted treatments for ESCC.
Purpose of the Study:
- To investigate the molecular landscape of ESCC, focusing on metabolic remodelling and its effect on the immune microenvironment.
- To identify novel therapeutic targets associated with metabolic alterations and immunosuppression in ESCC.
Main Methods:
- Integrated multi-omics analyses (metabolomics, proteomics, genomics, transcriptomics) were performed.
- ESCC patient cohorts were classified into subtypes based on metabolic and immune profiles.
- Molecular characteristics and mechanisms of identified ESCC subtypes were validated.
Main Results:
- Multi-omics analysis revealed distinct metabolic imbalances and protein dysregulation in ESCC.
- Three ESCC subtypes (S1, S2, S3) were identified, with the S3 subtype showing a significantly immunosuppressive microenvironment and poor prognosis.
- Creatine accumulation and hexokinase 3 (HK3) deficiency were identified as key biomarkers for the S3 subtype, driving M2-like macrophage polarization and tumor progression.
Conclusions:
- Metabolic remodelling significantly influences the immune microenvironment in ESCC.
- Targeting creatine metabolism and HK3 presents a potential strategy to reverse immunosuppression and enhance the efficacy of immunotherapy and targeted therapies in ESCC.
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