Exosomes in cancer therapy: Advances and current challenges

ABSTRACT

Cancer begins as a single cell. The corruption within the fundamental processes of this cell spreads outwards, invading and metastasizing, bringing death and earning cancer the sobriquet "The Emperor of all maladies". In 2020, one out of six deaths was caused by cancer. Globally, cancer is one of the leading causes of death, second only to cardiovascular diseases [1]. Advances in scientific discovery have led to a dizzying array of tools in our arsenal to combat it. Cancer treatment can extend its reach to the molecular level, tailoring treatment to the unique characteristics of a person's disease, and targeting specific molecular targets for a tumor type.
Exosomes, in turn, are a promising new avenue of treatment in a long line of scientific advances [2][3][4]. They are nothing more than extracellular vesicles of endosomal origin that help in intercellular communication [5]. Originally, exosomes were believed to simply be cellular cargo containers carrying deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), micro-ribonucleic acid (miRNA), proteins, and lipids. However recent research has given us dramatic insights into these seemingly unimportant tiny vesicles. Exosomes may serve as intercellular and systemic communicators with their composition unique based on the recipient microenvironment and cells. Exosomes are also produced by tumor cells -referred to as tumor-derived exosomes (TEXs). These may play a critical role in cancer, acting as signaling molecules [6]. In cancer, the signals from exosomes can affect the immune system by inhibiting the function and production of antigen-presenting cells, T cells, and natural killer cells. They may also increase the number of immune suppressor cells providing a fertile ground for the progression of neoplastic lesions [7,8]. TEXs mediate these immune support cancer cells to escape the immune survivance during cancer development.
On the other hand, TEXs could play a critical role in the diagnosis and prognosis of different types of cancer, including liver, gastric, breast, colorectal, ovarian, esophageal, and prostate cancer, etc. [8]. Circulating TEXs may open a new platform for liquid biopsy as they contain molecules characteristic of the parent malignant tissues [8,9]. Isolation of exosomes from body fluids such as urine, serum, plasma, saliva, and lymph are possible through microfluidics-based platforms [10] and innovative mechanisms such as acoustic [11] or electromagnetic isolation [12]. The release of exosomes coincides with the activation of autophagy [13]. They may serve as clinical biomarkers to monitor autophagy during cancer therapy. Exosomal release of proteins involved in the metastasis of cancer may for example be possible candidates for the progression and surveillance of lung [14] and breast cancer [15].
Exosomes may also serve to track treatment response assessment. It is worth noting here that tumor cells prevent their destruction with a degree of metabolic flexibility against traditional treatments. Tumor-associated exosomes are believed to contribute to this evasion through rising drug resistance in tumor cells [16]. Blocking the exosomal secretion pathway has shown promising results in reducing secretions of chaperone proteins that are high-value oncologic targets in cancer treatment [17]. Exosome-mediated communication can also be targeted using mechanisms and compounds that inhibit its uptake such as heparin, cytochalasin D, dynasore, or endocytosis inhibitors [18].
Drug delivery in cancer treatment has different limitations (biological barrier crossing, toxicity, and biocompatibility). Exosomes can contribute greatly to successfully circumventing these barriers as useful vectors for drug delivery of anticancer drugs, given that different nanoparticles can be combined with exosomes for targeted delivery to tumor cells [19]. Indeed, extracellular vesicles can function as nanosystems to deliver drugs, nucleic acids, proteins, and viruses, which could slow down the growth of tumor cells [20]. Dendritic cell-derived exosomes have already been previously shown to eradicate murine tumors, acting as a cell-free vaccine by priming cytotoxic T lymphocytes [21].
Exploiting and developing exosomes for delivering therapeutics is an unmet challenge in the fight against cancer. Commercial development of products of exosome research remains at an adolescent stage and invites serious conversation to conceptualize this emerging field in therapeutics. Despite the challenges related to exosome therapy, including difficulties in the production of a heterogeneous population, large-scale production, and the production of a cancer vaccine based on TEXs, important research is ongoing. The use of exosomes for solid tumor therapy and engineered exosomes as drug carriers are currently under clinical trials. Mesenchymal stem cell-derived exosomes, dendritic cell-derived exosomes, and educated immune cell-derived and plant-derived exosomes are being investigated for their effects on tumor cells. The ongoing clinical trials may unlock novel and precise exosome technology [20]. Despite all the barriers, this fascinating field walks side by side with precision cancer medicine, as well as looking towards related vaccine development [22].
In short, exosomes continue to hold great promise for noninvasive early-stage detection of cancer, sensing of the tumormicroenvironment, and intracellular imaging. Such vesicles are an extraordinary opportunity that can further progress previous research success to create sustainable mechanisms that can be translated from the laboratory to the clinic to combat the cancer burden. The next decade is expected to experience a rapid expansion in cancer treatment incorporating advances as our understanding of related biology grows. Ethical statement: Authors stated that ethics committee approval was not required for this study.

Declaration of interest: No conflict of interest is declared by authors.
Data sharing statement: Data supporting the findings and conclusions are available upon request from the corresponding author.