C9orf50 is a Targetable Spliceosome Regulator for Cancer Immunotherapy DOI Creative Commons
Tong Shao, Chuanyang Liu, Jingyu Kuang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Abstract Cancer cells harbor cell-intrinsic programs capable of sculpting immunogenic landscapes, yet molecular brakes that enforce immune evasion remain poorly defined. Here, we identify C9ORF50, a previously uncharacterized intrinsically disordered protein, as liquid-liquid phase separation-driven regulator RNA processing and actionable immunotherapy target. Genetic ablation C9ORF50 induces selective intron retention in spliceosome component transcripts, leading to cytoplasmic accumulation double-stranded (dsRNA). This dsRNA activates type I interferon pathway turn orchestrates chemokine secretory program critical for T cell recruitment. The resultant enhancement tumor immunogenicity reprogramming microenvironment drives robust antitumor immunity, effectively converting immunologically “cold” tumors “hot” phenotypes. Therapeutic targeting via interference achieved suppression syngeneic models, suggesting its translational relevance. Notably, exhibits tumor-predominant expression, with minimal baseline levels detected healthy tissues or populations, underscoring potential safety therapeutic Our study not only identifies novel LLPS-dependent splicing but also establishes it promising potentially safe target cancer immunotherapy.

Language: Английский

C9orf50 is a Targetable Spliceosome Regulator for Cancer Immunotherapy DOI Creative Commons
Tong Shao, Chuanyang Liu, Jingyu Kuang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Abstract Cancer cells harbor cell-intrinsic programs capable of sculpting immunogenic landscapes, yet molecular brakes that enforce immune evasion remain poorly defined. Here, we identify C9ORF50, a previously uncharacterized intrinsically disordered protein, as liquid-liquid phase separation-driven regulator RNA processing and actionable immunotherapy target. Genetic ablation C9ORF50 induces selective intron retention in spliceosome component transcripts, leading to cytoplasmic accumulation double-stranded (dsRNA). This dsRNA activates type I interferon pathway turn orchestrates chemokine secretory program critical for T cell recruitment. The resultant enhancement tumor immunogenicity reprogramming microenvironment drives robust antitumor immunity, effectively converting immunologically “cold” tumors “hot” phenotypes. Therapeutic targeting via interference achieved suppression syngeneic models, suggesting its translational relevance. Notably, exhibits tumor-predominant expression, with minimal baseline levels detected healthy tissues or populations, underscoring potential safety therapeutic Our study not only identifies novel LLPS-dependent splicing but also establishes it promising potentially safe target cancer immunotherapy.

Language: Английский

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