Deciphering CD8⁺ T cell exhaustion in human cancers through single-cell and spatial transcriptomics

Area of Science:

• Immunology
• Cancer Biology
• Genomics

Background:

• Exhausted CD8+ T cells (Tex) in the tumor microenvironment (TME) limit anti-tumor immune responses by upregulating inhibitory receptors and reducing cytotoxicity.
• Limited understanding of Tex genomic features and regulatory networks restricts the efficacy of immune checkpoint blockade (ICB) therapy, with only a minority of patients responding.
• Functional heterogeneity among Tex subpopulations complicates therapeutic strategies.

Purpose of the Study:

• To review recent advances in high-resolution omics technologies for dissecting Tex heterogeneity, functional features, and cellular interactions.
• To emphasize the importance of optimizing Tex-targeted immunotherapies for enhanced anti-tumor responses.
• To provide theoretical foundations for developing more effective cancer immunotherapies.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) for high-resolution transcriptomic profiling of Tex subpopulations.
• Spatial transcriptomics to map the spatial distribution and interaction networks of Tex within the TME.
• Integration of omics data to define genomic characteristics and regulatory networks of Tex.

Main Results:

• scRNA-seq identified diverse Tex subpopulations with distinct marker genes and regulatory pathways.
• Spatial transcriptomics revealed the impact of spatial heterogeneity on Tex functionality and interactions with tumor and immune cells.
• The dynamic and modifiable nature of Tex exhaustion, linked to tumor progression and therapeutic response, was highlighted.

Conclusions:

• High-resolution omics technologies are crucial for precisely dissecting Tex heterogeneity and functionality.
• Understanding Tex interactions and genomic features is vital for improving ICB therapy efficacy.
• Optimizing Tex-targeted strategies offers a promising direction for developing more effective anti-tumor immunotherapies.