Alternative Splicing-Mediated Resistance to Antibody-Based Therapies: Mechanisms and Emerging Therapeutic Strategies

Antibody-based therapeutics targeting tumor surface markers have transformed cancer treatment; however, their efficacy is frequently limited by tumor escape mechanisms such as antigen loss, phenotypic switching, and heterogeneous target expression. Beyond genetic or transcriptional changes, RNA alternative splicing (AS) has emerged as a central post-transcriptional mechanism driving antigenic diversity and immune escape. This review outlines how AS-generated isoforms remodel surface antigen structure and function across key therapeutic targets—including CD/19/CD20/CD22, EGFR/HER2, VEGF, and PD-1/PD-L1—thereby promoting resistance to monoclonal antibodies, antibody–drug conjugates, and immune checkpoint inhibitors. The aberrant activity of splicing regulators disrupts canonical exon selection, leading to altered receptor signaling or the secretion of soluble decoy isoforms that evade immune recognition. Emerging therapeutic strategies aim to counteract these processes through antisense oligonucleotide-mediated splicing correction, pharmacologic modulation of splicing regulators, and isoform-selective antibody or CAR-T designs. Collectively, understanding splicing-driven antigenic plasticity reveals an additional, dynamic layer of resistance regulation and provides a framework for developing RNA-informed precision antibody therapies designed to restore antigen expression, overcome immune escape, and enhance durable clinical responses.