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<p>Emerging evidence highlights that metastatic colorectal cancer (mCRC) can occur early in tumor progression, with its unique genomic characteristics contributing to an altered immune landscape. This study aims to elucidate the molecular and immune mechanisms that drive mCRC progression and therapeutic resistance. By leveraging multi-omics data, we examined immune infiltration, immune subtypes, tumor mutational burden, DNA methylation, differentially expressed genes, proteins, and non-coding RNAs. Our analysis revealed that mCRC exhibited significantly reduced leukocyte infiltration (median: 11.75% vs. 16.87% in non-metastatic colorectal cancer [nmCRC], p &lt; 0.001), diminished T cell receptor diversity, and a lower representation of the IFN-γ-dominant immune subtype (24.6% vs. 35.2%, p &lt; 0.001). The CIMP-high status, which overlaps with MSI-high, was rare in mCRC (4.6%) but more prevalent in nmCRC (14.5%). Key immunomodulators, including CXCL9, IFNG, and CTLA4, were downregulated, and notably, reduced expression of GZMA was associated with impaired immune surveillance. Additionally, tumor mutational burden (TMB) was lower in mCRC (4.2 vs. 6.8 mutations/Mb, p &lt; 0.001). Predicted neoantigens derived from MUC16 correlated with enhanced immune infiltration and prolonged survival (disease-free survival [DFS] HR = 0.69, p = 0.016). Epigenetic hypermethylation was found to silence CD74 and modulate CD274 expression. Proteomic analysis revealed dysregulated antigen processing, characterized by downregulation of TAP1 (HR = 1.9, p = 0.001), while non-coding RNAs such as miR-4746 and miR-3677 played roles in immune evasion through regulation of EDNRB and HMGB1. Overall, mCRC is characterized by an immune-cold phenotype driven by neoantigen depletion and loss of IFN-γ signaling. Our findings suggest that mutations in MUC16 and restoration of TAP1 represent promising therapeutic targets. Integrating multi-omics profiling may offer valuable insights for developing strategies to overcome immunotherapy resistance in metastatic disease.</p>

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Dysregulated immune microenvironment in metastatic colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年2月24日

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  • Shuaixing An,
  • Zhaojin Yu,
  • Jianping Li,
  • Minjie Wei

摘要

Emerging evidence highlights that metastatic colorectal cancer (mCRC) can occur early in tumor progression, with its unique genomic characteristics contributing to an altered immune landscape. This study aims to elucidate the molecular and immune mechanisms that drive mCRC progression and therapeutic resistance. By leveraging multi-omics data, we examined immune infiltration, immune subtypes, tumor mutational burden, DNA methylation, differentially expressed genes, proteins, and non-coding RNAs. Our analysis revealed that mCRC exhibited significantly reduced leukocyte infiltration (median: 11.75% vs. 16.87% in non-metastatic colorectal cancer [nmCRC], p < 0.001), diminished T cell receptor diversity, and a lower representation of the IFN-γ-dominant immune subtype (24.6% vs. 35.2%, p < 0.001). The CIMP-high status, which overlaps with MSI-high, was rare in mCRC (4.6%) but more prevalent in nmCRC (14.5%). Key immunomodulators, including CXCL9, IFNG, and CTLA4, were downregulated, and notably, reduced expression of GZMA was associated with impaired immune surveillance. Additionally, tumor mutational burden (TMB) was lower in mCRC (4.2 vs. 6.8 mutations/Mb, p < 0.001). Predicted neoantigens derived from MUC16 correlated with enhanced immune infiltration and prolonged survival (disease-free survival [DFS] HR = 0.69, p = 0.016). Epigenetic hypermethylation was found to silence CD74 and modulate CD274 expression. Proteomic analysis revealed dysregulated antigen processing, characterized by downregulation of TAP1 (HR = 1.9, p = 0.001), while non-coding RNAs such as miR-4746 and miR-3677 played roles in immune evasion through regulation of EDNRB and HMGB1. Overall, mCRC is characterized by an immune-cold phenotype driven by neoantigen depletion and loss of IFN-γ signaling. Our findings suggest that mutations in MUC16 and restoration of TAP1 represent promising therapeutic targets. Integrating multi-omics profiling may offer valuable insights for developing strategies to overcome immunotherapy resistance in metastatic disease.