ArticleExperimental hematology & oncology2025
Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction.
Article in Experimental hematology & oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- CD112 Lactylation Drives Dual Immune Evasion From CD8+ T Cells and NK Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- The human microbiome reshapes the breast cancer immune-metabolic-hormonal microenvironment.Frontiers in immunology · 2026Review
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Authors and funding
17 authors.
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Abstract
Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the histone methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.
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