Several of today’s cancer treatments are based on the immune system’s capacity to detect and destroy cells expressing neoantigens on major histocompatibility class-I molecules (MHC-I). Despite this, we still do not know the cell biology behind how antigenic peptide substrates (APSs) for the MHC-I pathway are produced. Indeed, there are few research fields with so many divergent views as the one concerning the source of APSs. This is quite remarkable considering their fundamental role in the immune systems’ capacity to detect and destroy virus-infected or transformed cells. A better understanding of the processes generating APSs and how these are regulated will shed light on the evolution of self-recognition and provide new targets for therapeutic intervention. We discuss the search for the elusive source of MHC-I peptides and highlight the cell biology that is still missing to explain how they are synthesised and where they come from.

当今的几种癌症治疗方法都是基于免疫系统检测和破坏在主要组织相容性 I 类分子 (MHC-I) 上表达新抗原的细胞的能力。尽管如此，我们仍然不知道 MHC-I 途径的抗原肽底物 (APS) 是如何产生的细胞生物学。事实上，很少有研究领域像有关 APS 来源的问题那样存在如此多的分歧。考虑到它们在免疫系统检测和破坏病毒感染或转化细胞的能力中的基本作用，这是相当引人注目的。更好地了解 APS 的生成过程以及这些过程的调节方式将有助于揭示自我认知的演变，并为治疗干预提供新的目标。我们讨论了寻找 MHC-I 肽的难以捉摸的来源，并强调了仍然缺乏解释它们如何合成和来自何处的细胞生物学。