Targeting the OxLDL-PPARG-ANGPTL4 axis in CD36+ cancer-associated fibroblasts with Vitamin E alleviated immune suppression and enhanced anti-PD-1 therapy efficacy in preclinical osteosarcoma models.
Targeting CD36+ cancer-associated fibroblasts with Vitamin E to scavenge OxLDL enhances the efficacy of PD-1 blockade in osteosarcoma preclinical models.
BACKGROUND: Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. RESULTS: We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CONCLUSIONS: CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma.
Zeng et al. (Thu,) conducted a other in Osteosarcoma (n=8). Vitamin E and anti-PD-1 therapy vs. Control or anti-PD-1 monotherapy was evaluated on Tumor growth and CD8+ T cell infiltration (preclinical models). Targeting the OxLDL-PPARG-ANGPTL4 axis in CD36+ cancer-associated fibroblasts with Vitamin E alleviated immune suppression and enhanced anti-PD-1 therapy efficacy in preclinical osteosarcoma models.