• The Effect of Hypoxia-Induced Exosomes on Anti-Tumor Immunity and Its Implication for Immunotherapy
  • Nikoo Navidi,1 Elahe sadat Fakhshuri,2 Reza Abolhasanzade,3 Ghazaleh Amini,4 Fereshteh Gholami,5,*
    1. Student Research Commitee, Iran University Of Medical Sciences, Tehran, Iran
    2. Student Research Committee, Islamic Azad University Karaj Branch, Karaj, Iran
    3. Student Research Commitee, Islamic Azad University Ardabil
    4. Student Research Committee , IslamicAzad University Falavarjan , Isfahan , iran
    5. Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran


  • Introduction: Hypoxia is a common feature of many solid tumors that is associated with tumor growth, treatment resistance, and mortality. Tumor cells in their microenvironment encounter low oxygen levels due to insufficient oxygen flow and physiological abnormalities in tumor vasculature, leading to normoxic, hypoxic, as well as necrotic areas. In most solid tumors, the average oxygen concentration is close to 10 mmHg, while in other tissues it reaches 40 and 60 mmHg. In addition to inducing metabolic reprogramming of tumor cells to adapt to the hypoxia of the tumor microenvironment (TME), hypoxia can also enhance tumor growth by affecting the secretion of exosomes. Exosomes are small vesicles with a membrane and a size of 30 to 100 nm, which are present in blood, urine, saliva, semen, serum, etc. Exosomes play an important role in a variety of important biological processes such as immune response and inflammation, pregnancy, tissue proliferation, blood coagulation and angiogenesis. They are also involved in pathological processes such as disorders of nervous disorders, cancer, infectious diseases, cardiovascular, etc. Cancer-related cells secrete more exosomes than healthy cells due to the need for intercellular communication or nutrient exchange. It is worth noting that hypoxia-induced exosome changes are present not only in tumor cells but also in various TME cells, including stromal cells and immune cells. Studies of these exosome properties in tumor pathogenesis have led to the development of therapeutic and diagnostic approaches using exosomes for cancer treatment. Exosomes have many advantages for the delivery of therapeutic agents such as small interfering RNAs, microRNAs, membrane associated proteins and chemotherapeutic compounds. Therefore, they are considered a prime candidate as a delivery tool for cancer therapy. Because exosomes provide an optimal microenvironment for the effective action of immunomodulatory agents, exosomes containing bioactive molecules have been designed as cancer immunotherapeutic that can effectively activate each stage of the cancer immune cycle to create cancer-specific immune success. In this review, we focused on the effects of hypoxia on exosome secretion.
  • Methods: In this review article, we collected the required data using keywords and using databases such as Google Scholar, PubMed, Scopus and ProQuest. In this study, the statistical population includes all the studies whose articles have been published until 2022. After reviewing the findings and evaluating the quality of the obtained data, 13 articles were analyzed.
  • Results: First, hypoxia-induced exosomes are not vesicles loaded with cellular debris, but key mediators of intercellular communication. Second, exosome cargoes differ in hypoxic and normoxic TMEs. Hypoxia may affect the biosynthesis, metabolic degradation, and post synthetic modification of cargoes and the efficiency of specific cargo sorting mechanisms. Under adverse TME conditions such as hypoxia, high glucose, and drug therapy, the cargo transported and delivered in the exosome is significantly altered, which in turn modulates immune cell function. Third, exosomes are secreted by immune cells such as DCs and chimeric antigen receptor T cells.
  • Conclusion: In recent years, anti-tumor immunotherapy, representing immune checkpoint inhibitors, has changed the treatment option for various tumor types. As previously mentioned, the infiltration and activation of immune cells in the TME is closely related to successful immunotherapy. Due to the role of exosomes in cancer progression and biological properties, exosomes have promising potential for cancer treatment. Therefore, understanding the effect of exosomes on the anti-tumor immune system can further increase the effect of immunotherapy. To date, several exosome-based cancer therapies have been studied and developed, including the use of natural immune cell-derived exosomes to suppress cancer cells, inhibition of cancer cell-derived exosome activity, and the use of exosomes as gene/drug carriers. However, there are significant challenges to overcome. First, the differences between exosomes from different sources are still unclear. Second, the number of exosome required to obtain a therapeutic effect may vary significantly among different cancers. Third, tumor scalability and heterogeneity may affect treatment outcome.
  • Keywords: Hypoxia, Exosomes, Anti-tumor immunity, Immunotherapy, Tumor microenvironment