Gene fusion neoantigens: Emerging targets for cancer immunotherapy

Tumor neoantigens play an important role in current cancer immunotherapies. The most commonly studied class of tumor neoantigens contains those derived from single-nucleotide variants (SNVs) and insertions or deletions (Indels). However, gene fusions are also ideal sources of tumor neoantigens, as they can form new open reading frames (ORFs). Compared with SNV and Indel (SNV&Indel) neoantigens, fusion gene neoantigens tend to be more immunogenic, have more targets per mutation, and are more broadly shared across different cancer types. As a result, they are an important class of tumor neoantigens and emerging targets for cancer immunotherapies, with uses as prognostic biomarkers of immune checkpoint blockade (ICB) and in the development of tumor vaccines, adoptive cell therapies and tumor immune microenvironment modulation. In this review, we introduce the chromosomal basis and characteristics of gene fusions. Then, we summarize the predictive tools, mutation burden and immunogenicity of gene fusion neoantigens. Further, we discuss applications and future improvements of gene fusion neoantigens with respect to current cancer immunotherapies and novel developments in cancer treatment. • Fusion neoantigens tend to have higher immunogenic potential than SNV&Indel. • Predicting ICB outcome needs to consider tumor fusion neoantigens. • Vaccine and adoptive cell therapy targeting fusion neoantigens are emerging. • Gene fusion neoantigens are more frequent in tumors with suppressive immune environments.