Immunometabolic coevolution defines unique microenvironmental niches in ccRCC

Area of Science:

• Oncology
• Metabolomics
• Immunology

Background:

• Tumor cell phenotypes and anti-tumor immunity depend on local metabolite availability.
• Intratumoral metabolite heterogeneity (IMH) and its consequences are not well understood.

Purpose of the Study:

• To investigate IMH in clear cell renal cell carcinoma (ccRCC).
• To identify metabolite biomarkers associated with therapeutic response.

Main Methods:

• Profiling of tumor and normal tissues from ccRCC patients.
• Analysis of intratumoral metabolite-RNA covariation.
• Inference of metabolomic profiles from RNA sequencing data of ccRCC patients in clinical trials.

Main Results:

• A common IMH pattern characterized by ferroptosis-associated metabolites was observed across patients.
• Immune cell composition, particularly myeloid cells, drove intratumoral metabolite variation.
• Metabolite biomarkers associated with response to anti-angiogenic agents were identified.

Conclusions:

• Local metabolic phenotypes are linked to the immune microenvironment and influence tumor evolution.
• Metabolomic profiles inferred from RNA sequencing can identify biomarkers for therapeutic sensitivity in ccRCC.