Single-cell and bulk transcriptome analyses reveal elevated amino acid metabolism promoting tumor-directed immune evasion in colorectal cancer

作者：Tian-Yue Sun, Yan Chen, Yan Chen, Ying-Xuan Chen, Ying-Xuan Chen · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1575829 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Immune cells in cancer

Introduction Colorectal cancer (CRC), the third most common cancer worldwide, often shows limited responsiveness to immunotherapy due to its predominantly immune-excluded phenotype. Despite increasing insights into the complex tumor microenvironment (TME), the metabolic heterogeneity of CRC cells and their interactions with tumor-infiltrating immune cells remain poorly understood. Methods We analyzed 46,374 epithelial cells from 17 CRC patients treated with PD-1 blockade to develop an amino acid (AA) metabolism score using the AUCell algorithm. This score was applied to a separate single-cell RNA sequencing (scRNA-seq) dataset from 23 CRC patients to investigate cell-cell interactions and functions of tumor-infiltrating immune cells, revealing distinct immune TME landscapes shaped by tumor metabolism. An in vitro co-culture assay of CRC cells and CD8 + T cells was performed to validate the findings. Additionally, LASSO and Cox regression analyses were conducted to construct an AA metabolism-related risk score for predicting prognosis and drug sensitivity across multiple bulk transcriptome cohorts. Results This study identified a link between elevated amino acid metabolism in CRC epithelial cells and resistance to PD-1 blockade therapy. A 31-gene AA score was developed by intersecting differentially expressed genes between responders and non-responders to PD-1 blockade with amino acid metabolism-related genes from the Molecular Signature Database (MSigDB). Using this score, 23...