Malignant melanoma is one of the most concerning malignant tumors because of its ability to spread early and aggressively. There is no effective treatment strategy for malignant melanoma, and the 5-year survival rate for melanoma patients under conventional treatment is 10–15%(Anestopoulos et al., 2022, Steininger et al., 2021). It is projected that the global incidence of melanoma will rise in the next 20 years. By 2040, there will be an estimated 510,000 new cases worldwide, with an increase of over 50% in the number of deaths, reaching 96,000 (Pavlick et al., 2023). Continuing elevated incidence rates and low five-year survival rates have prompted the development of new and effective therapeutic strategies for malignant melanoma.

The emergence of immunotherapy has greatly changed the treatment and prognosis of cutaneous melanoma (Santoni et al., 2022). A survey of relevant studies had shown that immune checkpoint inhibitors, either alone or in combination with different drugs, had led to significant breakthroughs in cancer treatment, thereby prolonging the survival of most tumor patients (Mollica et al., 2023). However, immune checkpoint inhibitors have a specific set of treatment-related toxicities, which are mainly caused by the misrecognition of self-antigens by the immune system(Santoni et al., 2023). Research indicated that patients with brain metastases (Glitza Oliva et al., 2018, Rizzo, 2022) and uveal melanoma (Rantala et al., 2022) had a poor prognosis. Therefore, there is an urgent need to develop more effective strategies to enhance the efficacy of immunotherapy in melanoma.

One approach is to combine nanomedicine with cancer immunotherapy to improve clinical response. Extracellular vesicles (EVs) are natural nanoscale to microscale membrane vesicles encapsulated by lipid bilayers, which play an important role in local and systemic cellular communication by exchanging proteins, lipids, and subsets of functional genetic material from donor cells (Becker et al., 2016, Greening et al., 2023, Wu et al., 2021).Recent studies have shown that EVs can be widely used as functional mediators of parent cells to regulate anti-tumor responses (Xu et al., 2020). EVs can be released by almost all types of cells, including tumor cells (Hessvik and Llorente, 2017). On the one hand, tumor cell-derived EVs can alter the function of different types of stromal cells, thereby promoting the growth and invasive behavior of cancer cells, on the other hand, they can inhibit the proliferation and activation of CD8 T cells, promote the expansion of regulatory T cells, and perform an immunosuppressive function (Li et al., 2021, Qiao et al., 2019, Xu et al., 2022), thus promoting the metastasis of tumor cells. In recent years, the anticancer functions of tumor cell-derived EVs have been continuously revealed, and they have gradually become a hotspot for cancer immunity research. Tumor cell-derived EVs carry major histocompatibility complex class I molecules (MHC I) and tumor antigens that can participate in antigen presentation and stimulation of T cells, triggering CD8 T cell-dependent antitumor responses (Giacobino et al., 2021, Naseri et al., 2020, Vergani et al., 2022, Warrier et al., 2019), This is one of the reasons why tumor cell-derived EVs are being used to treat tumors.

Dendritic cells (DCs) are the most powerful antigen-presenting cells in the body and are essential for the normal behavior of the immune system, because they play mediators between innate and adaptive immune responses (Giacobino et al., 2021). It has been shown that tumor cell-derived EVs activate anti-tumor immune effects mainly through stimulation of DCs maturation (Markov et al., 2019). Tumor cell-derived EVs present tumor-borne antigens to DCs, prompting DCs maturation, and mature DCs express antigenic peptides in the form of antigenic peptide-MHC molecular complexes on cell membranes, which interact with T cells through MHC-T cell receptor recognition and co-receptor engagement. Antigenic information is delivered to T cells, providing an initiating signal for the initialization of T cell activation (Saxena et al., 2021, Steinman, 2012, Xu et al., 2020).

In this study, we investigated the role of melanoma cell B16-F10-derived EVs (B16-EVs) in anti-tumor immunity. We found that B16-EVs, as tumor cell derivatives carried tumor antigens, not only stimulated the maturation of DCs and activated T cells to release IFN-γ, but also effectively inhibited tumor growth and metastasis through the activation of CD8 T cells. This study demonstrated that B16-EVs can elicit anti-tumor immune responses against melanoma. This suggested that anti-tumor active immunity triggered by tumor cell-derived EVs might be an effective strategy to inhibit cancer progression. Our research provided a new strategy for the future development of effective cancer vaccines or adjuvant immunotherapies based on tumor cell-derived EVs.