CircZNF609 inhibited bladder cancer immunotherapy sensitivity via enhancing fatty acid uptake through IGF2BP2/CD36 pathway.

Circular RNAs (circRNAs) are gaining attention for their involvement in immune escape and immunotherapy sensitivity regulation. CircZNF609 is a well-known oncogene in various solid tumours. Our previous research revealed its role in reducing the chemosensitivity of bladder cancer (BCa) to cisplatin. However, the underlying role of circZNF609 in BCa immune escape and immunotherapy sensitivity remains unknown. We conducted BCa cells-CD8 + T cells co-culture assays, cell line-derived xenograft and patient-derived xenograft mouse models with human immune reconstitution to further confirm the role of circZNF609 in BCa immune escape and immunotherapy sensitivity. Overexpression of circZNF609 promoted BCa immune escape in vitro and in vivo. Mechanistically, circZNF609 was bound to IGF2BP2, enhancing its interaction with the 3'-untranslated region of CD36. This increased the stability of the CD36 mRNA, leading to enhanced fatty acid uptake by BCa cells and fatty acid depletion within the tumour microenvironment. Additionally, the nuclear export of circZNF609 was regulated by DDX39B. CircZNF609 promoted immune escape and suppressed BCa immunotherapy sensitivity by regulating the newly identified circZNF609/IGF2BP2/CD36 cascade. Therefore, circZNF609 holds potential as both a biomarker and therapeutic target in BCa immunotherapy.