Non-canonical function of SCIMP restricts JAK1 activity to counteract immune evasion in bladder cancer

Background: Despite the fact that immunotherapy is reshaping the therapeutic landscape of bladder cancer, immune evasion remains a major obstacle to durable clinical benefit. Therefore, elucidating the mechanisms underlying immune resistance is essential for developing novel therapeutic strategies. Methods: In this study, we performed a genome-wide CRISPR-Cas9 screen in bladder cancer cells co-cultured with CD8+ T cells and identified the SLP adaptor and CSK-interacting membrane protein (SCIMP) as a key gene that enhances CD8+ T cell antitumor immunity. Results: SCIMP serves as a favorable prognostic biomarker in patients with bladder cancer treated with immunotherapy. Mechanistically, SCIMP restricts JAK1 phosphorylation in an adaptor-independent manner, suppressing the IFN-γ/JAK1/STAT5A/PD-L1 signaling axis. Meanwhile, YTHDF2 destabilizes the m6A-tagged SCIMP transcripts to reduce their expression. Remarkably, SCIMP synergizes with PD-1 blockade in suppressing tumor growth. Conclusions: Collectively, these findings reveal a previously unexplored non-canonical role of SCIMP in preventing immune evasion and provide a potential therapeutic target for bladder cancer.