Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma - A novel mechanism of immune evasion and its implications for precision immunotherapy

Sep 22, 2026

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Background and Purpose: Hepatocellular carcinoma (HCC) drives global cancer mortality through late detection and resistance, including limited effectiveness of immune checkpoint blockade (ICB). Tumor-derived exosomal PD-L1 suppresses T-cell function by engaging PD-1, inducing exhaustion and systemic immunosuppression. This study tested whether Annexin A2 (ANXA2) regulates exosomal PD-L1 in HCC to promote immune escape. Results: ANXA2 increased in HCC and linked to fewer CD8+ T cells and poor survival. ANXA2 knockout reduced exosome secretion and exosomal PD-L1, impairing suppression of CD8+ activation. ANXA2 loss slowed tumor growth in immunocompetent mice and reduced CD63 stability, implicating lysosome-associated turnover. Conclusions: ANXA2 enhances immune evasion via CD63-stabilized exosomal PD-L1, supporting a novel target to improve ICB efficacy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Tumor microenvironment and exosomal PD-L1

Need for identifying regulators of exosomal PD-L1 sorting

Role of Annexin A2 in tumor progression and resistance

Neoplasia 73 (2026) 101280 Contents lists available at ScienceDirect Neoplasia journal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo) | Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma: A novel mechanism of immune evasion and its implications for precision immunotherapy
Jian Zhang a,1, Ying Gu b,1, Fangchao Zhao c,d, Yong Chene, Yuqing Xia e, Dekang Gaof, Qiang Yuan a,*, Xuming Baia,*
a Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Rd, Suzhou 215004, China b Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Rd, Suzhou 215004, China c Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Rd, Shijiazhuang 050000, China d Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, No. 899, Ping Hai Rd, Suzhou 215006, China e Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Rd, Suzhou 215004, China f Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Rd, Suzhou 215004, China | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
Hepatocellular carcinoma Exosomal PD-L1 Annexin A2
Immune evasion T-cell suppression | | Background and Purpose: Hepatocellular 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.
Results: Bioinformatic 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.
Conclusions: ANXA2 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. | Introduction Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality globally, is characterized by late-stage diagnosis and therapeutic resistance, which contribute to its dismal prognosis [1]. While immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has provided clinical benefits for advanced HCC patients, objective response rates remain below 20%, with most patients developing resistance due to immune evasion mechanisms [2,3]. The immunosuppressive tumor microenvironment (TME) is a central determinant ofICB resistance, and exosomes—30–150 nm lipid bilayer vesicles released via multivesicular body (MVB)-plasma membrane fusion—have emerged as critical mediators of intercellular communication, capable of remodeling the

FAQs

How does ANXA2 affect exosomal PD-L1 in hepatocellular carcinoma?

ANXA2 modulates exosomal PD-L1 expression by maintaining CD63 protein stability, which supports PD-L1 incorporation into exosomes. ANXA2 knockout reduces exosome secretion and exosomal PD-L1 levels.

What experimental evidence links ANXA2 to immune evasion?

Bioinformatic analyses associate ANXA2 upregulation with fewer CD8+ T cells and poor survival. Functional assays show control exosomes suppress CD8+ T-cell activation, whereas exosomes from ANXA2 knockout cells do not.

Why is the study relevant to precision immunotherapy?

Because ANXA2-driven, tumor-specific regulation of exosomal PD-L1 can contribute to ICB resistance. Targeting this pathway may enhance ICB efficacy and improve responses across exosome-dependent cancers.

Sep 22, 2026

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