Targeting the NSUN5-circPPAP2A axis reverses immunosuppression and sensitizes renal cell carcinoma to anti-PD-1 therapy - PubMed
4 days ago
- #Immunotherapy resistance
- #RNA modification
- #Renal cell carcinoma
- NSUN5 is the predominant m5C methyltransferase in clear cell renal cell carcinoma (ccRCC), and its high expression predicts poor survival.
- The NSUN5/circPPAP2A/YBX1 axis enhances YBX1 nuclear translocation and phosphorylation, leading to transcriptional activation of HIF-2α.
- This axis promotes an immunosuppressive microenvironment by suppressing CD8+ T cell infiltration via downregulation of CCL5 and promoting T cell exhaustion via upregulation of TGFB1.
- Knockdown of NSUN5 or circPPAP2A synergizes with anti-PD-1 therapy, inhibiting tumor growth and restoring anti-tumor immunity.
- Targeting the NSUN5-circPPAP2A axis offers a novel combinatorial strategy to overcome resistance to both HIF-2α-targeted therapies and anti-PD-1 immunotherapy.