Glycolysis-Driven Immune Evasion in Microsatellite Instability-High Colorectal Cancer: An Integrated Single-Cell and...

Area of Science:

• Oncology
• Cancer Immunology
• Metabolic Reprogramming

Background:

• Microsatellite instability-high colorectal cancer (MSI-H CRC) presents hypermutated genomes and high neoantigen loads.
• Despite this, a substantial fraction of MSI-H CRC patients are resistant to immune checkpoint blockade (ICB).
• Tumor cell functional heterogeneity is implicated in immune evasion.

Purpose of the Study:

• To investigate tumor cell functional heterogeneity in MSI-H CRC.
• To understand the role of this heterogeneity in immune evasion and ICB resistance.
• To identify potential therapeutic strategies targeting metabolic pathways.

Main Methods:

• Integration of single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing.
• Identification of malignant epithelial subpopulations using copy number variation and non-negative matrix factorization.
• Functional characterization via gene set enrichment analysis and spatial mapping of immune and tumor cells.

Main Results:

• A glycolysis-enriched tumor subpopulation (MP2) was identified, co-localizing with immunosuppressive niches.
• These niches featured Treg accumulation, effector T-cell depletion, and FOLR2+ macrophages.
• MP2-high tumors correlated with ICB resistance and poor prognosis, driven by lactate secretion promoting immunosuppression.

Conclusions:

• Tumor cell-intrinsic glycolysis is a key driver of immune evasion in MSI-H CRC.
• Lactate secreted by MP2 cells promotes Treg differentiation and M2-like macrophage polarization.
• Metabolic targeting represents a promising strategy to overcome ICB resistance in MSI-H CRC.