Non-canonical and induced neoantigens as emerging sources of cancer-specific immunotherapy targets.

Immunotherapy has transformed cancer treatment, yet its clinical benefit remains limited in many tumors, particularly those with low mutational burden. Because most current immunotherapeutic strategies rely on neoantigen recognition, expanding the repertoire of targetable tumor-specific antigens is essential. In this review, we discuss non-canonical and therapy-induced neoantigens - derived from alternative splicing, RNA editing, transposable elements, and aberrant translation - as emerging sources of immunotherapy targets, with emphasis on their potential to improve the efficacy of current treatment approaches. We summarize recent evidence supporting the immunogenicity of corresponding neoepitopes and highlight therapy-induced antigen generation as a promising but underexplored opportunity. In particular, we focus on the impact of splicing dysregulation and chemotherapy-induced splicing alterations on neoepitope formation. We argue that integrating non-canonical and induced neoantigens into currently available immunotherapy approaches could improve antitumor efficacy and the specificity of resulting therapies, especially in tumors with limited mutational load.