Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Clear cell renal cell carcinoma (ccRCC) pathogenesis involves the von Hippel-Lindau tumor suppressor, leading to HIF-1α and HIF-2α activation.
• Existing models suggest HIF-2α promotes tumors, while HIF-1α suppresses them, but clinical relevance and hypoxia-associated factor (HAF) roles are understudied in ccRCC.

Purpose of the Study:

• To investigate the clinical significance of HAF and HIFs in ccRCC.
• To analyze the association of HAF/HIFs with tumor characteristics, patient outcomes, and anti-angiogenic therapy response.

Main Methods:

• Analysis of HAF/HIF expression in 380 ccRCC patient tissues, with validation in 72 and 57 additional patients.
• Utilized single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and immunohistochemistry (IHC) for detailed characterization.

Main Results:

• HIF-1α predominantly in tumor-associated macrophages (TAMs) correlated with high tumor grade, metastasis, poor survival, and anti-angiogenic therapy resistance.
• HAF and HIF-2α, primarily in tumor cells, were linked to low grade, reduced metastasis, and better survival.
• scRNA-seq and IHC confirmed HIF-1α expression in M2-polarized, CD163-positive TAMs.

Conclusions:

• TAM-derived HIF-1α plays a significant role in ccRCC progression and therapeutic resistance.
• Findings suggest re-evaluating HIF-1α as a prognostic marker and potential therapeutic target in ccRCC.