Demonstration of SLU7 as a new cancer target.

Cancer treatment remains challenging due to heterogeneous responses to immunotherapy across patients and tumor types. Innovative strategies are required to overcome immune evasion. We have identified the splicing factor SLU7 as essential for the survival of cancer cells from diverse origins. SLU7 knockdown induces R-loop accumulation, transcription-dependent genomic instability, DNA damage, and replication catastrophe, together with aberrant splicing and inhibition of nonsense-mediated mRNA decay (NMD) and/or DNA methylation. These alterations lead to the expression of neoantigens, interferon B1, endogenous retroviruses, and cancer-testis antigens, which would enhance tumor immunogenicity. Therefore, we propose SLU7 targeting as a dual-action therapy, combining direct tumor suppression with immune activation. We used organoids and various murine cancer models, including orthotopic liver tumors, and multiple molecular strategies, such as inducible CRISPR/Cas9 and shRNA, systemic delivery of chimeric siSLU7-nucleolin aptamers (APTASLU), and intratumoral injection of siSLU7-loaded nanoparticles alone or in combination with the immune checkpoint inhibitor anti-PD1. We show that distinct siSLU7 sequences and delivery platforms effectively inhibit the growth of tumors including liver orthotopic and human hepatocellular carcinoma, cholangiocarcinoma and colon carcinoma subcutaneous xenografts. Furthermore, SLU7 silencing may synergize with immune checkpoint inhibitors, amplifying anti-tumor responses. Our in vivo data demonstrate that SLU7 is a promising, versatile target for possibly diverse cancers. Its multimodal mechanism offers potential to overcome tumor heterogeneity, reverse immune tolerance, and enhance immunotherapy efficacy.