Single-Cell Atlas Reveals Tumorigenic Profiles and Immune Dynamics of Adrenal Incidentalomas.

Summary

Integrating 302,696 single cells across adrenal incidentaloma subtypes, the study delineates tumorigenic programs, highlights clusterin as a candidate biomarker for adrenocortical adenomas, and identifies MYCN-positive pheochromocytoma clusters linked to poorer survival. Distinct immune ecosystems suggest myeloid regulation in benign tumors and CD8+ T cell–driven activation/infiltration in malignant lesions.

Key Findings

• Integrated single-cell RNA-seq of 302,696 cells across nonfunctional adrenocortical adenomas, Conn’s syndrome, and pheochromocytomas.
• Identified clusterin as a candidate biomarker for adrenocortical adenomas and marked SF1 upregulation distinguishing cortical from medullary tumors.
• MYCN-positive pheochromocytoma clusters associated with poorer survival.
• Immune microenvironment differed by lesion type: myeloid-regulated benign tumors versus CD8+ T cell–driven activation/infiltration in malignant lesions.

Clinical Implications

Clusterin and SF1 signatures may aid in differentiating adrenocortical from medullary tumors and identifying high-risk pheochromocytomas (MYCN-positive); immune profiles could inform selection of immunomodulatory strategies.

Limitations

• Primarily cross-sectional profiling without interventional validation or longitudinal outcomes.
• Biomarker utility requires prospective clinical validation and standardized assays.

Future Directions

Prospective validation of clusterin/SF1 signatures and MYCN risk stratification; functional studies to test immune-ecosystem–guided therapies in adrenal tumors.