Sarcoma is a group of rare and heterogeneous malignant mesenchymal-derived tumors with over 200 histological subtypes having different molecular alterations, which can be generally classified into bone sarcoma and soft tissue sarcoma (de Heus et al., 2021). The incidence of sarcoma is approximately 70/106/year accounting for over 20% of all pediatric solid malignancies and less than 1% of all adult malignant cancers (de Pinieux et al., 2021, Strauss et al., 2021). For some subtypes, like osteosarcoma and Ewing’s sarcoma, children and teenagers are the most commonly affected groups (Strauss et al., 2021). In general, the prognosis of sarcoma is unsatisfactory, and patients with sarcoma have 5-year net survival rates of about 60% (Amadeo et al., 2022). The signs and symptoms of sarcoma vary depending on the location of the lesion, including a lump or mass, localized pain, swelling, limited mobility, fragility fracture, weight loss, and fatigue (George & Grimer, 2012). Currently, diagnosis for sarcoma is based on clinical manifestations and the results of scans and biopsy, which are non-specific and not timely, leading to a high rate of delayed diagnosis and treatment (George & Grimer, 2012). Early diagnosis and patient stratification are difficult in clinical settings without appropriate biomarkers. Non-invasive and specific tests that inform prognosis and longitudinal remission status also remain a persistent unmet need for sarcoma patients. Treatment of sarcoma still focuses on traditional surgery, chemotherapy, and radiotherapy, and the various subtypes of sarcoma determine varied therapeutic strategies, making sarcoma management difficult (Gronchi et al., 2021, Strauss et al., 2021). Improving patient survival has consistently proven to be a challenge.

To address these clinical hurdles in sarcoma, increasing attention has been turned to exosomes. Exosomes are extracellular vesicles enclosed by lipid bilayer membranes with a diameter of 30-150 nm. Various cells in the tumor microenvironment can release exosomes into extracellular space, and exosomes can be detected in body fluids, such as plasma, urine, and saliva (Han & Yi et al., 2021). Exosomes contain a varying assortment of proteins, nucleic acids, and lipid substances, which reflect the physiology and pathology states of parental cells (Mashouri et al., 2019). The lipid bilayer of exosomes establishes a stable structure and enables cargoes to resist enzymatic degradation in body fluids (Makino et al., 2013). To date, differential expression and diagnostic value of circulating exosomes have been reported in cancers of the lung, liver, breast, stomach, and among others (Hu et al., 2020, Lakshmi et al., 2021, Li et al., 2020, Tang et al., 2021). This evidence on the potential of exosomes in biofluids is transforming the field of clinical biomarkers. Additionally, one of the main problems during cancer treatment remains the specific targeting of tumor cells, affecting drug efficacy and toxicity. Exosomes, as intercellular vehicles with membrane components and ligands similar to the parental cells, play important roles in intercellular interactions and sarcoma pathogenesis (Min et al., 2016). Regulatory molecules can be targetedly transported by exosomes between sarcoma cells and cells in the tumor microenvironment, such as tumor-associated macrophages, fibroblasts, mesenchymal stem cells, and endothelial cells, leading to the immune-suppressive and tumor-promoting differentiation of microenvironment cells, the acquisition of malignant capacities in sarcoma cells, and remodeling of extracellular matrix (Araki et al., 2021, Avnet et al., 2021, Cheng et al., 2021, Mazumdar et al., 2020b, Tao et al., 2020, Zhang et al., 2021, Zhao et al., 2021). Sarcoma-derived exosomes induced macrophages to converse into M2-like macrophages, leading to immune suppression and pre-metastatic lung formation (Wolf-Dennen et al., 2020, Cheng et al., 2021). Exosomes from sarcoma also triggered the phenotypic conversion of fibroblasts, which promoted the local microenvironment remodeling and pre-metastatic lung formation contributing to the aggressive behaviors of sarcoma cells (Morita et al., 2020, Mazumdar et al., 2020b). Sarcoma-originated exosomes enhance the expression of angiogenic factors and reactivity to these factors in endothelial cells (Raimondi et al., 2020). Meanwhile, sarcoma cells integrate the exosomes released by these cells to decrease apoptosis, promote aggressiveness conversion, and enhance chemoresistance (Pan et al., 2021, Lee et al., 2021, Liu et al., 2021). Thus, exosomes play important roles in the survival of sarcoma cells, tumor local invasion and distant metastasis, tumor-immune interactions, angiogenesis, and therapy tolerance (Gassmann et al., 2021, Mazumdar et al., 2020a, Pan et al., 2021, Qin et al., 2020, Ucci et al., 2021, Zhong et al., 2021). Besides, the diverse microbial populations harbored in the human body orchestrate physiological processes and disease susceptibility, and the microbiome communities may influence the development, metastasis, and treatment response of malignancies (Sender et al., 2016, Cullin et al., 2021). Due to the effects of exosomes on tumorigenesis, interests have been focused on applying exosomes therapeutically by controlling exosome production or release, disrupting its cellular communicating procedures, and developing immune therapy applications (Bastos et al., 2018, Xia et al., 2020). Exosomes have been investigated as nanocarriers for anti-tumor agents and small molecules, such as microRNA and small interfering RNA (siRNA), in targeted therapy of lung cancer, colorectal cancer, breast cancer, etc. (Chadar et al., 2021, Liu et al., 2019, Wang et al., 2021b).

However, a consistent diagnostic signature of circulating exosomal molecules is not available in sarcoma, and the therapeutic advancement is unsatisfactory. Here, we provided a comprehensive summary of exosome applications in the liquid biopsy-based diagnosis and prognosis in sarcoma, and explore their implications in the delivery system, targeted therapy, and chemotherapy resistance of sarcoma (Fig. 1). Questions that have to be considered when applying exosomes in clinic are raised and some future research directions are proposed.