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TIM-3/Galectin-9 Immune Axis in Colorectal Cancer in Relation to KRAS, NRAS, BRAF, PIK3CA, AKT1 Mutations, MSI

Błażej Ochman1, Anna Kot1, Sylwia Mielcarska1

  • 1Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-808 Zabrze, Poland.

International Journal of Molecular Sciences
|July 29, 2025
PubMed

Insights

TIM-3 and Galectin-9 (Gal-9) are elevated in colorectal cancer (CRC), correlating with PIK3CA mutations and immune suppression. These proteins may serve as biomarkers for immunoevasive CRC tumors.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) exhibits complex interactions within its tumor microenvironment.
  • Immune checkpoints like TIM-3 and Galectin-9 (Gal-9) play critical roles in cancer progression.
  • Understanding these markers in relation to genetic mutations and immune profiles is crucial for therapeutic strategies.

Purpose of the Study:

  • To investigate the expression of TIM-3 and Gal-9 in CRC tissues.
  • To determine the association of TIM-3 and Gal-9 with oncogenic mutations (PIK3CA, KRAS, NRAS, BRAF, AKT1), MSI status, cytokine profiles, and transcriptional data.
  • To explore the potential of TIM-3 and Gal-9 as biomarkers for immunoevasive CRC phenotypes.

Main Methods:

  • Protein expression analysis of TIM-3 and Gal-9 in CRC tissues and matched non-tumor margins.
  • Correlation analysis with oncogenic mutations and MSI status.
  • Multiplex cytokine profiling and Gene Set Enrichment Analysis (GSEA).

Main Results:

  • TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to controls.
  • Elevated TIM-3 was associated with PIK3CA mutations, but not with KRAS, NRAS, BRAF, AKT1, or MSI status.
  • High TIM-3 and Gal-9 expression correlated with altered cytokine profiles (e.g., IL-10, IL-17) and GSEA revealed enrichment of cell cycle pathways and suppression of immune signatures (interferon, TNF-α/NFκB).

Conclusions:

  • Increased TIM-3 and Gal-9 expression in CRC indicates a shift towards proliferative activity and immune suppression.
  • These markers are associated with PIK3CA-mutant tumors, suggesting a specific immunoevasive phenotype.
  • TIM-3 and Gal-9 show potential as biomarkers for identifying immunoevasive CRC tumors, particularly those with PIK3CA mutations.
Keywords:
BRAFGalectin-9KRASNRASPIK3CATIM-3colorectal neoplasmsmicrosatellite instability (MSI)tumor immune microenvironment

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