N6-methyladenosine-modified RNF220 induces cisplatin resistance and immune escape via regulating PDE10A K48-linked ubiquitination in bladder cancer.

Bladder cancer (BCa) remains one of the most prevalent malignancies worldwide, with cisplatin-based combination chemotherapy as the cornerstone of adjuvant treatment. However, cisplatin resistance frequently arises in advanced BCa, limiting therapeutic efficacy. Comparative proteomic analysis of cisplatin-sensitive and -resistant BCa cells identified phosphodiesterase 10A (PDE10A) as significantly downregulated at the protein level in resistant cells, despite unchanged mRNA levels, indicating post-transcriptional regulation. Functional assays demonstrated that PDE10A enhanced cisplatin sensitivity by promoting apoptosis. Mechanistically, the E3 ubiquitin ligase RNF220 directly interacted with PDE10A, facilitating its ubiquitination and degradation under cisplatin-resistant conditions. RNF220 overexpression markedly reinforced cisplatin resistance in vitro and in vivo. Furthermore, N6-methyladenosine (m6A) modification mediated by METTL3 stabilized RNF220 mRNA in an IGF2BP2-dependent manner. Additionally, RNF220 promoted PD-L1 expression by destabilizing PDE10A, thereby facilitating immune evasion in BCa. These findings establish RNF220 as a pivotal ubiquitinase that drives both cisplatin resistance and immune escape through PDE10A destabilization, highlighting its potential as a therapeutic target to enhance chemotherapy and immunotherapy efficacy in advanced BCa.