Hyaluronidase: structure, mechanism of action, diseases and therapeutic targets

Abstract

Hyaluronidase (HAase), a family of enzymes critical for regulating physiological and pathological states, catalyzes the degradation of hyaluronic acid (HA), a key component of the extracellular matrix (ECM). By modulating ECM composition and cellular signaling pathways, HAase plays a pivotal role in diverse biological processes, including wound healing, tissue regeneration, and tumor progression. This review systematically elucidates the classification, biological sources, structural diversity, and catalytic mechanisms of HAase, emphasizing its dynamic involvement in disease pathogenesis and diagnostic potential. Furthermore, the article explores innovative therapeutic strategies centered on HAase modulation. HAase inhibitors emerge as promising tools for maintaining HA homeostasis, with implications in anti-inflammatory, antimicrobial, and antitumor therapies by blocking excessive HA degradation. Concurrently, HAase-mediated drug delivery systems represent a paradigm shift in overcoming biological barriers, enhancing bioavailability, and optimizing therapeutic outcomes through ECM remodeling. Notably, the synergy between HAase and immunotherapeutic modalities, such as checkpoint inhibitors and adoptive cell therapies, demonstrates synergistic antitumor effects by reshaping the tumor microenvironment (TME) and augmenting immune cell infiltration. Nevertheless, numerous challenges persist in the clinical application of hyaluronidase, including its immunogenicity, safety, application limitations and ethical considerations. This review synthesizes current research advances and unresolved issues, integrating molecular insights with translational perspectives, aiming to provide a more comprehensive and in-depth understanding of hyaluronidase and to advance clinical therapeutic strategies for hyaluronidase.

Keywords: Extracellular matrix; Hyaluronic acid; Hyaluronidase; Tumor immunotherapy; Tumor microenvironment.

Fig. 1

Schematic of the chemical structure of hyaluronic acid, and the classification of hyaluronidase based on enzyme specificity and catalytic mode

Fig. 2

Molecular mechanisms of hyaluronic acid degradation by three distinct classes of hyaluronidases. a. EC 3.2.1.35 hydrolyzes β−1,4-glycosidic bonds via a retention mechanism; b. EC 3.2.1.36 hydrolyzes β−1,3-glycosidic bonds via a retention mechanism;c. EC 4.2.2.1 cleaves β−1,4-glycosidic bonds through β-elimination

Fig. 3

Interaction of hyaluronic acid and cellular receptor swaying.CD44 and RHAMM signaling pathways mediate the most complex and important cell-substrate interactions

Fig. 4

Effect of hyaluronidase-mediated degradation of hyaluronan on tumor microenvironment. HA degradation leads to ECM structural relaxation, alleviates the TME hypoxia state, and improves oxygenation and nutrient supply by promoting Neovascularization formation, which is beneficial to the development of the TME, it promotes the infiltration and activation of immune effector cells, including T cells, NK cells, DCs, and reduces the recruitment of MDSCs, which is also accompanied by the release of inflammatory factors such as TNF-α,IL-1β, and IL-6

Fig. 5

Mechanism diagrams of various tumor immunotherapy methods.a. Immune checkpoint inhibitor therapy reactivates the antitumor activity of T cells, thereby enhancing the Immune system’s attack on tumor cells; b. The patient’s immune cells are transformed, activated, and expanded in vitro and then re-infused into the patient to clear the tumor, including CAR-T and TCR-T therapies, among others; c: Mechanism of action of cancer vaccines; d. Different kinds of Bispecific antibodies; e. OVs are generally thought to mediate anti-tumor activity through two different mechanisms of action, one is selective replication within tumor cells, which has a direct lytic effect on n tumor cells; The second is to induce systemic anti-tumor immunity and anti-immune escape, including promoting The release of pathogen-related molecular patterns (PAMPs), danger-associated molecular pattern signals (DAMPs), and cytokines from tumor cells, thereby activating antigen-specific CD4 + and CD8 + T cell responses to regulate TME; f. Cytokine therapy works by activating immune cells through antigen capture and presentation