Alternative Splicing Modulates Tumor Immune Responses and Immunotherapy Efficacy

Cancer immunotherapy has revolutionized treatment, yet a significant portion of patients exhibit primary or acquired resistance, highlighting a critical gap in understanding and predicting therapeutic efficacy. Alternative splicing, a fundamental post-transcriptional mechanism, dramatically expands transcriptomic and proteomic diversity, playing crucial roles in normal cellular physiology, including complex immune regulation. Dysregulation of this precise process in tumor cells and their microenvironment is increasingly recognized as a key factor influencing tumor immunogenicity and shaping the immune landscape. This review explores how aberrant alternative splicing contributes to immune evasion and modulates responses to current cancer immunotherapies, offering new avenues for intervention.

This comprehensive review synthesizes and critically evaluates the rapidly expanding body of evidence demonstrating the multifaceted impact of dysregulated alternative splicing on tumor immunity. The authors meticulously examine how alternative splicing events can alter the expression and peptide repertoire of tumor antigens, directly influencing major histocompatibility complex (MHC)-mediated antigen presentation. Furthermore, the review details how specific splicing programs generate novel immunomodulatory isoforms that actively promote immune evasion. It also investigates how cell type-specific splicing programs intricately regulate the phenotypes and functions of various intratumoral immune and stromal cells, including T cells, antigen-presenting cells, myeloid cells, and fibroblasts, thereby shaping the overall anti-tumor immune response. The authors integrate findings on how specific splicing signatures and isoform-level alterations are associated with clinical responses to immunotherapy, particularly immune checkpoint blockade, highlighting their potential as predictive biomarkers.

The review establishes that dysregulated alternative splicing is a pervasive and significant factor influencing tumor immunogenicity, profoundly shaping the immune landscape of the tumor microenvironment, and critically modulating responses to cancer immunotherapy. It highlights that alternative splicing can directly alter the expression and peptide repertoire of tumor antigens, thereby impacting major histocompatibility complex (MHC)-mediated antigen presentation efficiency. Crucially, the review details how aberrant splicing generates specific immunomodulatory isoforms that actively promote immune evasion by tumor cells, allowing them to escape immune surveillance.

Cell type-specific splicing programs are identified as critical regulators of the phenotypes and functions of various intratumoral immune and stromal cells, including T cells, antigen-presenting cells, myeloid cells, and fibroblasts, profoundly shaping the anti-tumor response and influencing therapeutic outcomes. Furthermore, the review emphasizes that specific splicing signatures and isoform-level alterations are consistently associated with clinical responses to immunotherapy, particularly immune checkpoint blockade, underscoring their potential as novel predictive and prognostic biomarkers. A deeper understanding of splicing dysregulation in tumor immunity is presented as essential for advancing biomarker development, improving patient stratification, and enabling the therapeutic targeting of aberrant RNA processing pathways in cancer.