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已发表论文
微卫星高度不稳定型结直肠癌中由糖酵解驱动的免疫逃逸：一项整合单细胞和空间转录组学的研究
Authors Li C, Cai P, Zeng H, Li J, Hu H, Zhang J , Wu Z, Qin G, Deng Y
Received 2 May 2025
Accepted for publication 14 August 2025
Published 18 September 2025 Volume 2025:18 Pages 1027—1042
DOI https://doi.org/10.2147/OTT.S538018
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr John Riches
Chenchen Li,1,2,* Peicong Cai,3,* Hengda Zeng,4,* Jianxia Li,1,2 Huabin Hu,1,2 Jianwei Zhang,1,2 Zehua Wu,1,2 Ge Qin,1,2 Yanhong Deng1,2
1Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yanhong Deng, Email dengyanh@mail.sysu.edu.cn Ge Qin, Email qing6@mail.sysu.edu.cn
Purpose: Microsatellite instability-high colorectal cancer is characterized by hypermutated genomes and high neoantigen loads, yet a significant proportion of patients exhibit resistance to immune checkpoint blockade. This study aims to investigate tumor cell functional heterogeneity and its role in immune evasion.
Patients and Methods: We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing from microsatellite instability-high colorectal cancer patients. After quality control, normalization, and clustering, malignant epithelial subpopulations were identified through copy number variation analysis and non-negative matrix factorization. Functional characterization employed gene set enrichment analysis. Spatial transcriptomics clarified immune cell and tumor subpopulation localization, and survival analyses assessed prognostic implications.
Results: We identified a glycolysis-enriched tumor subpopulation (MP2) that co-localized with immunosuppressive niches marked by Treg accumulation, effector T-cell depletion, and FOLR2+ tumor-associated macrophages. MP2-high tumors were associated with immune checkpoint blockade resistance and poor prognosis. Mechanistically, MP2 cells secreted lactate, promoting Treg differentiation and macrophage polarization toward an immunosuppressive phenotype. Spatial transcriptomics revealed the precise organization of these lactate-rich, immune-excluded niches within tumors.
Conclusion: These findings establish tumor cell-intrinsic glycolysis as a key driver of immune evasion in microsatellite instability-high colorectal cancer and propose metabolic targeting as a strategy to overcome immune checkpoint blockade resistance.
Keywords: colorectal cancer, immune checkpoint blockade, immune evasion, tumor microenvironment, glycolysis, single-cell RNA sequencing, spatial transcriptomics
1Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yanhong Deng, Email dengyanh@mail.sysu.edu.cn Ge Qin, Email qing6@mail.sysu.edu.cn
Purpose: Microsatellite instability-high colorectal cancer is characterized by hypermutated genomes and high neoantigen loads, yet a significant proportion of patients exhibit resistance to immune checkpoint blockade. This study aims to investigate tumor cell functional heterogeneity and its role in immune evasion.
Patients and Methods: We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing from microsatellite instability-high colorectal cancer patients. After quality control, normalization, and clustering, malignant epithelial subpopulations were identified through copy number variation analysis and non-negative matrix factorization. Functional characterization employed gene set enrichment analysis. Spatial transcriptomics clarified immune cell and tumor subpopulation localization, and survival analyses assessed prognostic implications.
Results: We identified a glycolysis-enriched tumor subpopulation (MP2) that co-localized with immunosuppressive niches marked by Treg accumulation, effector T-cell depletion, and FOLR2+ tumor-associated macrophages. MP2-high tumors were associated with immune checkpoint blockade resistance and poor prognosis. Mechanistically, MP2 cells secreted lactate, promoting Treg differentiation and macrophage polarization toward an immunosuppressive phenotype. Spatial transcriptomics revealed the precise organization of these lactate-rich, immune-excluded niches within tumors.
Conclusion: These findings establish tumor cell-intrinsic glycolysis as a key driver of immune evasion in microsatellite instability-high colorectal cancer and propose metabolic targeting as a strategy to overcome immune checkpoint blockade resistance.
Keywords: colorectal cancer, immune checkpoint blockade, immune evasion, tumor microenvironment, glycolysis, single-cell RNA sequencing, spatial transcriptomics