Single-Cell Transcriptomic Profiling Reveals That Macrophage-Induced Angiogenesis Contributes to Immunotherapy...

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally.
• The tumor microenvironment (TME) significantly impacts HCC treatment outcomes, particularly immunotherapy response.
• Resistance to PD-1/PD-L1 blockade, a key immunotherapy strategy, remains a major clinical challenge in HCC.

Purpose of the Study:

• To identify cellular mechanisms underlying resistance to PD-1/PD-L1 blockade in HCC.
• To characterize novel macrophage populations associated with immunotherapy non-response.
• To elucidate the molecular pathways driving an immunosuppressive TME in resistant HCC.

Main Methods:

• Single-cell transcriptomic profiling of HCC tumors.
• Analysis of macrophage populations and their gene expression profiles.
• Transcriptional regulatory network analysis to identify key drivers.

Main Results:

• A distinct NFKBIZ+ M0 macrophage subset was identified in HCC non-responders to anti-PD-1 therapy.
• These macrophages display a hypoxia-induced phenotype, secreting VEGFA and HBEGF to promote angiogenesis.
• Elevated expression of CXCL2, CXCL3, and CXCL8 by these macrophages creates an immunosuppressive TME.
• FOSB-VEGFA and FOS-HBEGF signaling pathways were identified as key regulators of this pathogenic phenotype.

Conclusions:

• NFKBIZ+ macrophages represent a novel mechanism linking hypoxia, angiogenesis, and immune evasion in HCC.
• This macrophage subset is critically involved in resistance to PD-1 blockade therapy.
• Targeting NFKBIZ+ macrophages or associated pathways may offer strategies to overcome immunotherapy resistance in HCC.