Unlocking the secrets of the immunopeptidome: MHC molecules, ncRNA peptides, and vesicles in immune response.

The immunopeptidome, a diverse set of peptides presented by Major Histocompatibility Complex (MHC) molecules, is a critical component of immune recognition and response. This review article delves into the mechanisms of peptide presentation by MHC molecules, particularly emphasizing the roles of ncRNA-derived peptides and extracellular vesicles (EVs) in shaping the immunopeptidome landscape. We explore established and emerging insights into MHC molecule interactions with peptides, including the dynamics of peptide loading, transport, and the influence of cellular and genetic variations. The article highlights novel research on non-coding RNA (ncRNA)-derived peptides, which challenge conventional views of antigen processing and presentation and the role of EVs in transporting these peptides, thereby modulating immune responses at remote body sites. This novel research not only challenges conventional views but also opens up new avenues for understanding immune responses. Furthermore, we discuss the implications of these mechanisms in developing therapeutic strategies, particularly for cancer immunotherapy. By conducting a comprehensive analysis of current literature and advanced methodologies in immunopeptidomics, this review aims to deepen the understanding of the complex interplay between MHC peptide presentation and the immune system, offering new perspectives on potential diagnostic and therapeutic applications. Additionally, the interactions between ncRNA-derived peptides and EVs provide a mechanism for the enhanced surface presentation of these peptides and highlight a novel pathway for their systemic distribution, potentially altering immune surveillance and therapeutic landscapes.