伦敦大学学院癌症研究所Kevin Litchfield团队宣布他们的研究显示，非细胞因子介导的mRNA衰变抑制重塑癌症免疫肽。相关论文于2026年4月8日发表在《免疫学》杂志上。

该研究组研究了失调的RNA加工对新抗原产生的贡献。利用来自1000名患者的多组学和检查点抑制剂（CPI）反应数据，小组发现无意义介导的mRNA衰变（NMD）途径激酶SMG1活性降低是CPI反应改善的预测因子。通过SMG1靶向含有过早终止密码子的稳定转录本抑制NMD，这些转录本大多数是非突变起源的。这重塑了主要组织相容性复合体I类（MHC I类）结合的免疫肽穹窿，并将新抗原丰度增加到与高突变负担肿瘤相当的水平。在功能上，NMD抑制在体外驱动抗原依赖性T细胞介导的肿瘤细胞杀伤，在体外促进患者衍生模型中组织驻留T细胞的活化，并提高CPI在体内的疗效。他们的研究结果表明，NMD抑制是一种利用以前无法获得的规范和非规范新抗原的策略，具有增加肿瘤免疫原性的潜力。

据了解，DNA突变是免疫治疗中新表位的一个很好的特征。

附：英文原文

Title: Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

Author: Roberto Vendramin, Hongchang Fu, Shanila Fernandez Patel, Yue Zhao, Danwen Qian, Lorena Ligammari, Osnat Bartok, Polina Greenberg, Ronen Levy, Andrea Castro, Krupa Thakkar, Jun Murai, Wei-Ting Lu, Christopher C.T. Sng, Chen Weller, Gordon Beattie, Amandeep Bhamra, Roc Farriol-Duran, Despoina Karagianni, Marcellus Augustine, Krijn K. Dijkstra, Christopher L. Pinder, Benjamin S. Simpson, Gordon Weng-Kit Cheung, Felipe Galvez-Cancino, Petra Vlckova, Silvia Surinova, Manuel Rodriguez-Justo, Mansi Shah, Nicholas McGranahan, Jeremy G. Carlton, Eva Grnroos, James L. Reading, Yardena Samuels, Charles Swanton, Sergio A. Quezada, Kevin Litchfield

Issue&Volume: 2026-04-08

Abstract: DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

DOI: 10.1016/j.immuni.2026.02.005

Source: https://www.cell.com/immunity/abstract/S1074-7613(26)00075-0