Esophageal cancer (EC) ranks eighth among the most common cancers in the world. There are two main histological subtypes of EC according to their epidemiology and pathology: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Among them, ESCC accounts for the vast majority of EC cases worldwide [1,2]. Because the early symptom are not obvious, most patients with EC are diagnosed at an advanced stage, and the overall survival rate is <20% [3]. Although some progress has been made in the diagnosis and treatment of EC, the mortality rate has not been reduced significantly [4]. Therefore, further understanding of regulatory mechanism is urgent for the effective treatment of EC.

The interaction between tumor cells and other cells in the tumor microenvironment is the key to tumor progression. Tumor-associated macrophages (TAMs) are the abundant immune cells. They promote promotes tumor invasion and migration by suppressing immunity and promoting angiogenesis and extracellular matrix remodeling [5]. Macrophages respond to microenvironmental signals, resulting in a high degree of functional and phenotypic heterogeneity. They are differentiated into two functional subtypes under different stimuli: classically activated M1 macrophages and alternatively activated M2 macrophages [6]. M1 macrophages have inflammatory and anti-tumor effects; they express interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS). M2 macrophages express CD163, CD206, IL-10 and arginase-1 (ARG-1), which can regulate adaptive Th2 immunity, promote angiogenesis and tissue repair, have anti-inflammatory effects, and are conducive to tumor growth [6]. TAMs are typical M2 macrophages; however, how tumor cells transform macrophages into anti-inflammatory M2 macrophages is unclear.

Hyaluronidase 1 (HYAL1), a hyaluronic acid (HA)-degrading endoglycosidase, hydrolyzes high-molecular-weight HA fragments into low-molecular-weight HA to affect the physiological and pathological function of HA [7]. Low-molecular-weight HA promotes inflammation, angiogenesis and tumorigenesis [[8], [9], [10]]. HYAL1 acts as a tumor molecular marker of laryngeal cancer [11]. HYAL1 is involved in modulating growth, adhesion, invasion, cell cycle and angiogenesis of cancer cells [[12], [13], [14], [15], [16], [17]]. Besides, HYAL1 expression is upregulated in prostate cancer and the exosomes of prostate tumor cells contain HYAL1; these exosomes can enhance prostate stromal cell motility [18]. Nevertheless, very little is known about whether HYAL1 exerts a regulatory role in the progression of EC.

In the present study, we confirmed the presence of HYAL1 in exosomes secreted by an ESCC cell line (EC109), by coculturing EC109 cells and macrophages. Subsequently, we performed loss-of function and gain-of-function experiments to study the role of cancer-derived exosomes containing HYAL1 in macrophage polarization and cancer cell functions and to explore its putative underlying mechanism. Our study provides a theoretical basis and effective solution for ESCC diagnosis and treatment.