Nature biomedical engineering · 2026
Programmable mRNA 3'UTR engineering restores MHC-I and overcomes immune evasion in prostate cancer.
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Huang Furong, Yuan Fuwen, Li Kexin, Cui Ya, Li Lei, Ye Wenbin, Cui Zhifen, Yan Jingyue, Chen Qiang, Nicchitta Christopher, Zhang Yuebao, Hankey William, Everitt Jeffrey, Huang Kai-Lieh, Wang Mu-En, Chen Ming, Huang Jiaoti, Wang Hongyan, Wagner Eric J, Lu Xin, Dong Yizhou, Li Wei, Wang Qianben
Аннотация
Immune-cold tumours such as prostate cancer often resist immune checkpoint therapies (ICT) due to impaired antigen presentation via major histocompatibility complex class I (MHC-I). While MHC-I downregulation is a common immune evasion mechanism, no approved therapies selectively restore MHC-I expression in tumours. We developed a programmable RNA engineering platform, termed the 3'UTR CRISPR/dCas13 Engineering System (3'UTRCES), to precisely manipulate mRNA alternative polyadenylation (APA) in vivo. We identified tumour-specific 3'UTR shortening of the E3 ligase adaptor SPSB1 as a driver of MHC-I degradation via SPSB1-mediated ubiquitination, without affecting PD-L1. Lipid nanoparticle (LNP)-delivered 3'UTRCES reversed SPSB1 3'UTR shortening, restored MHC-I expression and sensitized tumours to ICT in syngeneic mice. These effects were elicited by MHC-I-dependent increases in CD8 T cell infiltration and antitumour cytotoxic activity. Our findings reveal APA-driven MHC-I suppression as a previously unrecognized mechanism of immune escape and establish LNP-3'UTRCES as a versatile platform for post-transcriptional RNA engineering in cancer.