Alternative splicing: from tumorigenesis to neoantigen-mediated cancer immunotherapy

Alternative splicing (AS) is a crucial post-transcriptional regulatory mechanism that is frequently disrupted in cancer, leading to the generation of tumor-specific splice variants. These aberrant splicing events, often driven by mutations in splice sites or splicing factors (SFs), produce abnormal mRNA transcripts and protein isoforms that contribute to tumor initiation, progression, and immune evasion. Recent advancements in cancer immunotherapy have positioned AS-derived neoantigens as a novel and promising class of tumor-specific targets. These neoepitopes significantly expand the pool of immunogenic antigens for mRNA vaccines and adoptive cell transfer therapies, triggering robust and targeted anti-tumor immune responses. This review offers a comprehensive overview of the molecular mechanisms driving the generation of AS-derived neoantigens, their tumorigenic and immunological properties, and the antigen processing and presentation pathways involved. Additionally, we discuss emerging therapeutic strategies that exploit these neoantigens, such as splicing modulation and personalized immunotherapies, while also addressing current challenges and future prospects for translating AS-derived neoantigens into precision cancer immunotherapy.