Moonlighting ERAP Aminopeptidases in Cancer: Beyond Antigen Processing

Cancer immunotherapy has transformed the treatment of multiple malignancies; however, primary and acquired resistance remain major clinical challenges. Because effective immune recognition depends on the repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules, increasing attention has focused on the antigen processing and presentation pathway as a therapeutic target to enhance tumor immunogenicity. Among its key regulators, the endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 shape the MHC-I immunopeptidome by trimming peptide precursors before antigen presentation. Beyond this canonical function, accumulating evidence indicates that ERAP aminopeptidases are multifunctional proteins involved in inflammation, angiogenesis, ER stress responses, cell migration, and tumor-intrinsic signaling. These moonlighting activities suggest that ERAP enzymes influence cancer progression through both immune-dependent and immune-independent mechanisms. Recent advances in medicinal chemistry have enabled the development of selective ERAP1 inhibitors, leading to the first clinical evaluation of this therapeutic strategy and providing early clinical evidence that pharmacological modulation of antigen processing may complement existing immunotherapies. In this review, we summarize the multiple functions of ERAP aminopeptidases in cancer, discuss their role in regulating adaptive and innate immune responses, and highlight emerging therapeutic strategies and future challenges for exploiting ERAP-targeted interventions in precision immuno-oncology.