The peptide-loading complex (PLC) is a pivotal endoplasmic reticulum (ER) protein machinery that facilitates peptide translocation, editing, and loading onto major histocompatibility complex class I (MHC-I) to allow recognition of infected or transformed cells by CD8⁺ cytotoxic T lymphocytes (CTLs). PLC comprises the peptide transporter complex formed of transporters associated with antigen processing (TAP1/2), the adapter protein tapasin, chaperones such as calreticulin (CRT) and ERp57, and β2-microglobulin (β2M), ensuring the proper assembly of MHC-I/peptide complexes for subsequent antigen presentation on the cell surface. In cancer, tumorigenesis often involves structural malfunctions and transcriptional, post-transcriptional, and epigenetic modifications that impair the functioning of PLC proteins. This eventually causes loss of MHC-I cell-surface expression, failure of antigen presentation, and escape from CTL-mediated immunosurveillance. Although malfunctions in antigen-processing machineries are well known, herein we provide an overview of the PLC as a major determinant of tumor immune escape and a potential therapy target. In this regard, recent evidence indicates that individual PLC components not only affect MHC-I/antigen presentation but also influence tumor development and progression, immune evasion, and treatment resistance. Furthermore, we explore existing or evolving therapeutic approaches to recover/reprogram PLC functions such as IFN-γ-induced PLC activation, TAP1 and tapasin gene therapy, epigenetics-based treatments such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), and microRNA targeting strategy.