Loss of peripheral tolerance and consequent autoreactivity against non-mutated neoepitopes can emerge from a number of protein modifications associated with altered cellular homeostasis, encompassing: (1) the direct replacement of one or more amino acids during translation, (2) peptide splicing within the proteasome, endosomes/lysosomes, other protease-containing compartments, (3) a variety of enzymatic or non-enzymatic post-translational protein modifications (PTMs) such as citrullination, oxidation and glycation, and (4) altered protease activity and consequent generation of novel cleavage products. AA, amino acid; APC, antigen-presenting cell; ER, endoplasmic reticulum.