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Mesenchymal stem cell (MSC)-dependent biological effects in the tumor microenvironment mainly rely on the activity of MSC-sourced microRNAs (MSC-miRNAs) which modulate protein synthesis in target tumor cells, endothelial cells and tumor-infiltrated immune cells, regulating their phenotype and function. Several MSC-sourced miRNAs (miR-221, miR-23b, miR-21-5p, miR-222/223, miR-15a miR-424, miR-30b, miR-30c) possess tumor-promoting properties and are able to enhance viability, invasiveness and metastatic potential of malignant cells, induce proliferation and sprouting of tumor endothelial cells and suppress effector functions of cytotoxic tumor-infiltrated immune cells, crucially contributing to the rapid growth and progression of tumor tissue. On the contrary, MSCs also produce "anti-tumorigenic" miRNAs (miR-100, miR-222-3p, miR-146b miR-302a, miR-338-5p, miR-100-5p and miR-1246) which suppress tumor growth and progression by: Up-regulating expression of chemoresistance-related genes in tumor cells, by suppressing neo-angiogenesis and by inducing generation of tumorotoxic phenotypes in tumor-infiltrated lymphocytes. In this review article, we summarize the current knowledge about molecular mechanisms that are responsible for MSC-miRNA-dependent alterations of intracellular signaling in tumor and immune cells and we discuss different insights regarding the therapeutic potential of MSC-derived miRNAs in cancer treatment., (©The Author(s) 2023. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Due to their immunoregulatory properties and capacity for multi-lineage differentiation, mesenchymal stem cells (MSCs) have been used as new therapeutic agents in regenerative medicine. Numerous lifestyle habits and behavioral risk factors may modulate metabolic and cell growth signaling pathways in MSCs, affecting their phenotype and function. Accordingly, identification of these factors and minimization of their influence on viability and function of transplanted MSCs may greatly contribute to their better therapeutic efficacy. A large number of experimental and clinical studies have demonstrated the detrimental effects of cigarette smoke and nicotine on proliferation, homing, chondrogenic and osteogenic differentiation of MSCs. Cigarette smoke down-regulates expression of chemokine receptors and modulates activity of anti-oxidative enzymes in MSCs, while nicotine impairs synthesis of transcriptional factors that regulate the cell cycle, metabolism, migration, chondrogenesis and osteogenesis. In this review article, we summarize current knowledge about molecular mechanisms that are responsible for cigarette smoke and nicotine-dependent modulation of MSCs' therapeutic potential.