Single-Cell Dissection of the Tumor Microenvironment

How single-cell genomics is uncovering the cellular complexity of the tumor microenvironment, from exhausted T cells to tumor-associated macrophages.

The Tumor Microenvironment (TME)

Tumors are not just masses of malignant cells — they are complex ecosystems comprising cancer cells, immune cells, fibroblasts, endothelial cells, and extracellular matrix. The composition and state of this tumor microenvironment (TME) profoundly influences disease progression and treatment response.

What scRNA-seq Reveals

Single-cell profiling of the TME has uncovered:

Immune Compartment

• CD8+ T cell exhaustion gradients — Progressive loss of effector function marked by TOX, LAG3, and PDCD1 expression
• Regulatory T cells (Tregs) — Immunosuppressive populations enriched in the tumor core
• Tumor-associated macrophages (TAMs) — Polarization along a spectrum from M1-like (anti-tumor) to M2-like (pro-tumor)

Stromal Compartment

• Cancer-associated fibroblasts (CAFs) — Multiple subtypes with distinct roles in immune exclusion, matrix remodeling, and angiogenesis
• Endothelial heterogeneity — Tumor vasculature with abnormal transcriptional programs

Clinical Implications

Understanding TME composition at single-cell resolution enables:

• Biomarker discovery for immunotherapy response prediction
• Rational combination therapy design targeting multiple TME components
• Patient stratification based on immune cell states rather than bulk signatures

Key Resources

• Comprehensive human tumor atlases (e.g., HTAN, Tabula Sapiens)
• Pan-cancer single-cell studies providing cross-tumor-type insights