Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating...

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Liver metastasis (LM) is a major cause of mortality in metastatic colorectal cancer (mCRC).
• Limited understanding exists regarding the role of senescent and exhausted immune cells in LM development.
• Targeted therapy and immunotherapy efficacy is hindered by LM in mCRC.

Purpose of the Study:

• Investigate the contribution of senescent and exhausted immune cells to liver metastasis in mCRC.
• Elucidate the molecular mechanisms driving LM development.
• Develop a prognostic risk model for mCRC patients.

Main Methods:

• Single-cell sequencing data from primary colorectal cancer (pCRC) and matched LM tissues.
• Identification of senescent and exhausted immune cells.
• Enrichment analysis, cell communication, and trajectory analysis.
• In vitro experiments to validate findings.
• Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms for prognostic model development.

Main Results:

• Senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) were identified as key senescent and exhausted immune cells.
• SMCs and TEXs activate downstream transcription factors via ANGPTL4-SDC1/SDC4, promoting epithelial-mesenchymal transition (EMT) and LM.
• In vitro experiments confirmed the role of SMCs and TEXs in LM development.
• A prognostic risk model was developed and validated using 12 machine learning algorithms.

Conclusions:

• This study reveals molecular mechanisms of LM in CRC, highlighting the role of senescent and exhausted immune cells.
• A regulatory network implicating senescent/exhausted immune cells in EMT and LM development was constructed.
• The findings provide insights into potential therapeutic targets for mCRC with liver metastasis.