• Melanoma-derived versican upregulates pyruvate carboxylase (PCB) in tumor-associated macrophages (TAMs) under normoxia via the TLR2-MyD88-RelB signaling axis.
• Blocking the versican-TLR2-MyD88-RelB pathway reverses PCB upregulation and impairs TAM-mediated tumor cell clearance, highlighting its therapeutic potential.
• This study reveals a novel mechanism for reactivating TAMs under normoxic conditions, offering a strategy to enhance anti-tumor immunity without the side effects of systemic TLR activation.
• The findings provide potential molecular targets (versican, TLR2, MyD88, RelB, PCB) for developing immunotherapies aimed at reorienting TAMs toward an anti-tumor phenotype.