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Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells\u2019 interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.<\/jats:p>","DOI":"10.1007\/s13402-025-01042-z","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T08:43:12Z","timestamp":1739176992000},"page":"539-557","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer"],"prefix":"10.1007","volume":"48","author":[{"given":"Ozel","family":"Capik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer Faruk","family":"Karatas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"1042_CR1","doi-asserted-by":"publisher","first-page":"5619472","DOI":"10.1155\/2017\/5619472","volume":"2017","author":"P.M. 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