ArticleNeoplasia (New York, N.Y.)2026
Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma: A novel mechanism of immune evasion and its implications for precision immunotherapy.
Article in Neoplasia (New York, N.Y.), 2026. 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.
- Review
- Regulation of immune tolerance in hepatocellular carcinoma by liver diseases: a review.Infectious agents and cancer · 2026Review
- Integrated Bulk and Single-Cell Transcriptomic Analysis Reveals Xenobiotic Metabolism Genes Drive Progression From Liver Cirrhosis to Hepatocellular Carcinoma.Human mutation · 2026Article
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8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeHepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths globally due to late diagnosis and resistance to therapies, including immune checkpoint blockade (ICB). Tumor-derived exosomes carrying programmed death-ligand 1 (PD-L1) have emerged as key mediators of immune evasion by binding PD-1 on T cells, thereby inducing T cell exhaustion and systemic immunosuppression. This study investigated whether Annexin A2 (ANXA2) modulates exosomal PD-L1 expression in HCC cells to inhibit T-cell function and promote immune escape.
resultsBioinformatic analyses (TIMER2.0, TCGA) showed ANXA2 upregulation in HCC, correlating with fewer CD8⁺ T cells and poor survival. ANXA2 knockout (KO) in Hepa1-6 cells reduced exosome secretion and exosomal PD-L1, confirmed by EM, nanoparticle tracking, and WB. Exosomes from controls suppressed CD8⁺ T cell activation (reducing CD69, IL-2, IFN-γ, TNF-α), while KO exosomes did not. ANXA2 KO tumors grew slower in immunocompetent C57BL/6 J mice but not in immunodeficient BALB/c Nude mice, highlighting immune dependence. ANXA2 depletion reduced CD63 protein stability without affecting mRNA. CD63 re-expression in KO cells restored exosomal PD-L1, indicating ANXA2 maintains CD63 stability for PD-L1 exosomal incorporation. Transcriptomic and pharmacologic evidence further supported a role for lysosome-associated turnover in CD63 loss upon ANXA2 depletion.
conclusionsANXA2 drives HCC immune evasion by upregulating exosomal PD-L1 via CD63 stabilization, offering a novel target to enhance ICB efficacy. This work highlights a tumor-specific exosome regulation mechanism, with potential implications for immunotherapy across exosome-dependent cancers.
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