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<p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with pulmonary metastasis representing a critical determinant of poor prognosis in advanced disease. Although therapeutic strategies have improved, survival outcomes for CRC patients with lung metastases remain limited, underscoring the urgent need for robust prognostic biomarkers and innovative immunotherapeutic approaches. In this study, we employed an integrative computational framework to identify prognostic molecular signatures associated with CRC pulmonary metastasis and to design a rational multi-epitope vaccine (MEV) targeting key chemokines. Differential gene expression analysis of two GEO datasets (GSE181537 and GSE250000) using GEO2R identified five significantly upregulated C-X-C motif chemokines: CXCL1, CXCL3, CXCL5, CXCL8, and CXCL12. Functional enrichment and protein–protein interaction network analyses revealed their central roles in immune regulation, chemotaxis, inflammatory signaling, and cancer progression pathways. Survival and immune infiltration analyses further demonstrated their prognostic relevance and association with the tumor immune microenvironment. Immunoinformatics-based epitope prediction identified high-affinity cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B-cell epitopes, which were rigorously screened for antigenicity, non-allergenicity, non-toxicity, and interferon-γ induction potential. Selected epitopes were assembled into a chimeric MEV construct using appropriate linkers and immune-stimulatory adjuvants. Structural modeling, molecular docking, and molecular dynamics simulations confirmed stable binding interactions between the vaccine construct and Toll-like receptors TLR2 and TLR4. In silico immune simulations predicted robust humoral and cellular immune responses with the establishment of immunological memory. This integrative bioinformatics and immunoinformatics study identifies immune-associated CXC chemokines as promising prognostic biomarkers in CRC pulmonary metastasis and proposes a rationally designed multi-epitope vaccine candidate for further experimental validation and potential preclinical development in CRC immunotherapy.</p> Graphical Abstract <p></p>

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Decoding the role of CXC chemokines in pulmonary metastasis of colorectal cancer using integrative computational approaches

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Peng Meng,
  • Fengjuan Zhang,
  • Shan Li,
  • Xiaodong Fan,
  • Xiaoping Qian

摘要

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with pulmonary metastasis representing a critical determinant of poor prognosis in advanced disease. Although therapeutic strategies have improved, survival outcomes for CRC patients with lung metastases remain limited, underscoring the urgent need for robust prognostic biomarkers and innovative immunotherapeutic approaches. In this study, we employed an integrative computational framework to identify prognostic molecular signatures associated with CRC pulmonary metastasis and to design a rational multi-epitope vaccine (MEV) targeting key chemokines. Differential gene expression analysis of two GEO datasets (GSE181537 and GSE250000) using GEO2R identified five significantly upregulated C-X-C motif chemokines: CXCL1, CXCL3, CXCL5, CXCL8, and CXCL12. Functional enrichment and protein–protein interaction network analyses revealed their central roles in immune regulation, chemotaxis, inflammatory signaling, and cancer progression pathways. Survival and immune infiltration analyses further demonstrated their prognostic relevance and association with the tumor immune microenvironment. Immunoinformatics-based epitope prediction identified high-affinity cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B-cell epitopes, which were rigorously screened for antigenicity, non-allergenicity, non-toxicity, and interferon-γ induction potential. Selected epitopes were assembled into a chimeric MEV construct using appropriate linkers and immune-stimulatory adjuvants. Structural modeling, molecular docking, and molecular dynamics simulations confirmed stable binding interactions between the vaccine construct and Toll-like receptors TLR2 and TLR4. In silico immune simulations predicted robust humoral and cellular immune responses with the establishment of immunological memory. This integrative bioinformatics and immunoinformatics study identifies immune-associated CXC chemokines as promising prognostic biomarkers in CRC pulmonary metastasis and proposes a rationally designed multi-epitope vaccine candidate for further experimental validation and potential preclinical development in CRC immunotherapy.

Graphical Abstract