The emerging roles of alternative splicing in modulating tumor immune responses and immunotherapies

Alternative splicing is a fundamental mechanism that expands transcriptomic and proteomic diversity and contributes to multiple biological processes, including immune regulation. Increasing evidence shows that dysregulated alternative splicing influences tumor immunogenicity, the immune landscape of the tumor microenvironment, and responses to cancer immunotherapy. Alternative splicing can alter the expression and peptide repertoire of tumor antigens, modulate major histocompatibility complex-mediated antigen presentation, and generate immunomodulatory isoforms that promote immune evasion. In addition, cell type-specific splicing programs regulate the phenotypes and functions of intratumoral immune and stromal cells, including T cells, antigen-presenting cells, myeloid cells, and fibroblasts. Splicing signatures and isoform-level alterations are also associated with clinical responses to immunotherapy, particularly immune checkpoint blockade. A better understanding of splicing dysregulation in tumor immunity may improve biomarker development, patient stratification, and therapeutic targeting of aberrant RNA processing. Overall, alternative splicing is an important regulator of tumor-immune interactions and a potential target in cancer immunotherapy.