Peritumoural adipose tissue drives immune evasion in colorectal cancer via adipose-mesenchymal transformation.

Summary

Single-cell RNA sequencing of peritumoural visceral adipose tissue (tVAT) revealed a lymphocyte-rich niche that diverts tumour-specific CD8+ T cells via the CXCL12–CXCR4 axis. Tumour-derived cues induce adipose-mesenchymal transformation, generating CXCL12-secreting adipose-derived CAFs. Targeting adipose–tumour interactions enhanced the diagnostic and therapeutic performance of anti-PD-1 therapy.

Key Findings

• tVAT exhibits a highly immune-infiltrated microenvironment enriched with tumour-specific CD8+ T cells.
• tVAT competes with tumours for immunocytes by activating the CXCL12–CXCR4 axis, promoting immune escape.
• Tumour-derived factors induce adipose-mesenchymal transformation, generating adipose-derived CAFs that secrete abundant CXCL12.
• Targeting adipose–tumour interaction substantially enhances diagnostic and therapeutic efficacy of anti-PD-1 therapy.

Clinical Implications

Combining CXCR4 blockade or strategies disrupting adipose-mesenchymal transformation with PD-1 inhibitors could restore anti-tumour immunity. Imaging/biopsy of tVAT may refine patient selection and response monitoring.

Limitations

• Evidence is centered on colorectal cancer; generalizability to other cancers remains to be tested.
• Interventional data appear limited in scope and duration; long-term clinical outcomes are not reported.

Future Directions

Prospective trials combining CXCR4 inhibitors or stroma-directed therapies with PD-1 blockade, and development of tVAT imaging/biomarker strategies to stratify responders.