Targeting OxLDL-mediated CD36 + CAF reprogramming potentiates PD-1 immunotherapy in osteosarcoma

Area of Science:

• Oncology
• Immunology
• Cancer Metabolism

Background:

• Osteosarcoma exhibits poor response to PD-1 blockade due to an immunosuppressive tumor microenvironment (TME).
• The precise role of cancer-associated fibroblasts (CAFs) in osteosarcoma immunosuppression remains unclear.

Purpose of the Study:

• Investigate the mechanisms by which CAFs contribute to immune suppression in osteosarcoma.
• Determine the impact of CAF-derived factors on CD8+ T cell function and immunotherapy response.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of osteosarcoma tissues from patients receiving neoadjuvant chemotherapy and anti-PD-1 therapy.
• Analysis of cellular composition, gene expression, and signaling pathways within the TME.
• Functional assays, binding validation, and in vivo mouse models to assess CAF-mediated effects on T cells.

Main Results:

• Identified CD36+ CAFs with activated PPARG-FABP4 axis, facilitating oxidized low-density lipoprotein (OxLDL) uptake.
• Discovered OxLDL-driven ANGPTL4 secretion by CAFs, which activates JAK2-STAT3 in CD8+ T cells, causing exhaustion.
• Demonstrated that Vitamin E (VitE) scavenges OxLDL, improves TME, boosts CD8+ T cell infiltration, and synergizes with PD-1 blockade in vivo.

Conclusions:

• CD36+ CAFs promote osteosarcoma immune evasion through the OxLDL-PPARG-ANGPTL4 metabolic pathway, leading to CD8+ T cell exhaustion and immunotherapy resistance.
• Targeting this CAF-driven metabolic reprogramming with VitE can overcome immune suppression and enhance anti-PD-1 therapy efficacy.
• These findings support the development of metabolism-based combination strategies for osteosarcoma treatment.