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Immunol."],"abstract":"<jats:p>Chemoresistance and the immune-cold tumor microenvironment are major barriers to durable cancer control, yet they frequently emerge from overlapping mitochondrial adaptations selected by cytotoxic stress. In resistant tumors, mitochondria regulate oxidative phosphorylation (OXPHOS), redox buffering, apoptosis thresholds, organelle quality control, and metabolite overflow, while also shaping how antitumor immune cells experience nutrient deprivation, hypoxia, acidosis, and chronic danger signaling. Rather than assuming a single causal chain, this review distinguishes three non-equivalent relationships: direct suppression by mitochondria-derived signals, parallel emergence under shared selective pressures, and reverse causation in which immune exclusion itself facilitates mitochondrial adaptation. Within this framework, we synthesize evidence that mitochondrial adaptations support residual disease through OXPHOS dependence, mitochondrial dynamics, mitophagy, redox control, and metabolite-driven epigenetic remodeling, while concurrently reshaping T-cell, macrophage, and dendritic-cell function through lactate and acid stress, succinate, fumarate, 2-hydroxyglutarate (2-HG), adenosine, and mitochondrial DNA (mtDNA)-dependent innate immune signaling. We further highlight key determinants that influence whether mtDNA-STING signaling becomes immunogenic or suppressive, including timing, cell source, subcellular localization, and the dominant responding immune compartment. Finally, we discuss translational strategies to disrupt this mitochondria-immune interface, with emphasis on host and tumor heterogeneity, biomarker-guided selection, and treatment timing when combining with chemotherapy, mitochondrial targeting, and immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1872804","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:41:39Z","timestamp":1785130899000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial metabolic reprogramming at the interface of chemoresistance and immune-cold tumor states"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanfang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Oncology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China","place":["Changsha, 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