Alternative Splicing Overcomes Immune Therapy Resistance
The Hidden Puzzle of Immune Checkpoint Resistance: Alternative Splicing
While the majority of cancer patients respond to immune checkpoint blockade therapy, a subset exhibits primary non‑response or develops resistance during treatment. Identifying the underlying mechanisms of this resistance remains a major challenge.
Innovative Approach Uncovers Splicing Mechanisms
The research team meticulously tracked how spliceosomes and cis‑ and trans‑acting factors within the tumor microenvironment recombine checkpoint genes. They demonstrated a causal relationship whereby exon skipping alters receptor and ligand domains, thereby blocking signal transduction.
Next‑Generation Therapeutic Strategies Targeting Splicing
We propose a novel combination therapy that employs soluble isoforms as biomarkers and delivers soluble decoys via oncolytic viruses. Additionally, antisense oligonucleotides, splicing modulators, and CRISPR‑based correction technologies demonstrate potential to overcome resistance.
A New Turning Point for Future Cancer Therapy
If splicing correction strategies are translated into the clinic, they could substantially reduce current treatment failure rates. Ultimately, personalized immunotherapy may become the standard of care, enabling a larger proportion of patients to overcome cancer.
Immune checkpoint blockade (ICB) therapy has revolutionized oncology, yet its clinical efficacy remains limited due to primary and acquired resistance. Alternative splicing (AS), a fundamental post-transcriptional regulatory mechanism in eukaryotic gene expression, has been shown to profoundly remodel immune checkpoint molecules, driving immune evasion and ICB resistance. In this review, we systematically categorize immune checkpoint splicing based on splicing events, evolutionary conservation, altered domains, and functional impacts. We propose a new feature of immune checkpoint splicing, transmembrane exon splicing strategy. Mechanistically, we explain how dysregulated spliceosomes, cis-acting elements, and trans-acting factors within the tumor microenvironment orchestrate these splicing events, impacting ligand/receptor interactions and downstream immune signaling. Therapeutically, soluble isoforms serve as diagnostic/prognostic biomarkers. Engineered oncolytic viruses expressing soluble decoys offer novel combination strategies. Emerging therapeutic approaches, including antisense oligonucleotides, splicing modulators, RNA interference, and CRISPR/Cas systems, show promise for directly targeting aberrant splicing to overcome ICB resistance.
This study precisely elucidates why immune checkpoint blockade therapy fails in a subset of patients and leads to resistance. Leveraging these insights to develop personalized splicing correction therapies could enable more patients to overcome cancer.