{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:12:27Z","timestamp":1778857947793,"version":"3.51.4"},"reference-count":113,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1\u03b1, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC\u2013immune synapses, identifying \u201cmetabolic hotspots\u201d associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC\u2013immune interactions in metastatic cancer.<\/jats:p>","DOI":"10.3390\/cancers18101611","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T14:19:29Z","timestamp":1778854769000},"page":"1611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Hijacking and MicroRNA Crosstalk: Cancer Stem Cell-Mediated Immune Evasion and Metabolic Plasticity in the Tumor Microenvironment"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9833-7976","authenticated-orcid":false,"given":"Maziar","family":"Ashrafian Bonab","sequence":"first","affiliation":[{"name":"School of Geography and Natural Sciences, Faculty of Science and Environment, Northumbria University, Newcastle NE1 8ST, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4314-0722","authenticated-orcid":false,"given":"Shahrzad","family":"Salehi","sequence":"additional","affiliation":[{"name":"Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Tehran 14197331, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amirreza","family":"Aghababaie","sequence":"additional","affiliation":[{"name":"Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Tehran 14197331, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9603-5756","authenticated-orcid":false,"given":"Ali","family":"Amini","sequence":"additional","affiliation":[{"name":"Biology Department, American University, Washington, DC 20016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoda","family":"Alizadeh","sequence":"additional","affiliation":[{"name":"Department of Biosciences, College of Health, Medicine and Life Sciences, Brunel University, Kingston Campus, Uxbridge, London UB8 3PH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1266-1602","authenticated-orcid":false,"given":"Babak","family":"Behnam","sequence":"additional","affiliation":[{"name":"Floret Center for Advanced Genomics and Bioinformatics Research, Lagos 100282, Nigeria"},{"name":"Avicenna Biotech Research, Clarksburg, MD 20871, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Papadaki, S., and Magklara, A. 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