bims-mitrat 2026-08-09 papers

Crit Rev Oncol Hematol. 2026 Aug 06. pii: S1040-8428(26)00417-8. [Epub ahead of print] 105530

Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.

Sijia Feng, Yanan Hu, Shuqing Li, Yuqiao Chang, Zhenwei Li, Yanting Liu, Kai Xu.

Mitochondrial transfer has emerged as a previously underappreciated layer of intercellular communication within the tumor microenvironment. Accumulating evidence demonstrates its contribution to the metabolic and functional plasticity of both tumor and immune cells. Rather than representing a rare stochastic event, mitochondrial exchange occurs across multiple cell types-including cancer cells, stromal cells, and infiltrating immune cells-via distinct structures such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and transient cell fusion events. In tumor cells, acquisition of exogenous mitochondria is commonly associated with enhanced oxidative phosphorylation (OXPHOS), improved metabolic adaptation, and increased tolerance to therapeutic stress. Conversely, immune cells that undergo mitochondrial depletion or receive dysfunctional mitochondria frequently display impaired bioenergetic capacity and diminished effector function, thereby contributing to immune dysfunction in the TME. Recent advances in intravital imaging, single-cell technologies, and lineage tracing have provided compelling evidence that mitochondrial transfer is a dynamic, context-dependent and often directional process. Beyond metabolic effects, mitochondrial components, particularly mitochondrial DNA (mtDNA), can engage innate immune pathways including TLR9, NLRP3, and cGAS-STING, thus modulating inflammatory signaling and antitumor immunity. Overall, mitochondrial transfer functions as a bidirectional regulator of immunometabolic states in cancer, with potential either to support tumor progression or to modulate immune responses, depending on cellular context. Understanding the molecular determinants governing this process may offer opportunities to selectively target pathological mitochondrial exchange or to exploit it for therapeutic benefit in cancer immunotherapy. This comprehensive review examines the molecular mechanisms, immunological consequences, and therapeutic implications of mitochondrial transfer in cancer.

Keywords: extracellular vesicles; metabolism; mitochondrial transfer; tumor immune microenvironment; tunneling nanotubes

DOI: https://doi.org/10.1016/j.critrevonc.2026.105530

Transl Oncol. 2026 Aug 07. pii: S1936-5233(26)00250-0. [Epub ahead of print]72 102913

Intercellular mitochondrial exchange shapes tumor evolution, microenvironment adaptation, and therapeutic vulnerabilities.

Zhiyong Wu, Jianhao Bai, Aiqin Chang, Tianyu Wang, Yuan Liu, Hong Yu.

Mitochondrial transfer has emerged as a previously underappreciated mode of intercellular communication with major implications for tumor biology. Beyond their cell-autonomous roles in bioenergetics and signalling, mitochondria can be exchanged between cells as intact organelles or as mitochondrial cargo, thereby reshaping the metabolic state, stress tolerance and therapy responsiveness of recipient cells. In tumors, mitochondrial transfer can buffer oxidative stress, compensate for mtDNA damage and restore oxidative phosphorylation, enabling metabolic plasticity and contributing to immune dysfunction within the tumor microenvironment. This review synthesized current evidence for the structural routes and regulatory logic of mitochondrial exchange in cancer, spanning actin-based tunneling nanotubes, extracellular vesicle-mediated export and uptake, and other contact-dependent mechanisms. We highlight actionable "gatekeepers" that constrain transfer efficiency, including conduit biogenesis programs, MIRO1/2-TRAK-motor coupling that licenses mitochondrial trafficking, and EV biogenesis/uptake modules, as well as microenvironmental triggers such as hypoxia and redox stress. We also evaluate emerging methodological standards required to distinguish bona fide organelle transfer from dye leakage or indirect cargo exchange, and discuss how orthogonal validation (genetic reporters, mtDNA barcoding and functional rescue assays) can improve rigor and comparability across studies. By integrating current findings, this article aims to provide a theoretical foundation and strategic guidance for targeting tumor metabolic regulation and improving precision oncology approaches.

Keywords: Immune evasion; Mitochondrial transfer; Therapeutic strategies; Tumor metabolic reprogramming; Tumor microenvironment; Tunneling nanotubes

DOI: https://doi.org/10.1016/j.tranon.2026.102913

Redox Biol. 2026 Aug 04. pii: S2213-2317(26)00337-X. [Epub ahead of print]96 104338

Mitochondria as programmable redox rheostats: Advancing from transplantation to bioengineered organelle therapeutics.

Vikky Awasthi, Eric Lalu, Fatma Saaoud, Aasthika Das, Pawan Sharma, Ellyes Adnane, Glenn Gerhard, Suyog Mokashi, Hong Wang, Rihab Bouchareb.

Mitochondria are the primary arbiters of cellular redox homeostasis, bioenergetic flux, and programmed cell death. Their dysfunction, characterized by excessive reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and collapsed membrane potential, is a hallmark of diverse pathologies, including ischemia-reperfusion injury, neurodegeneration, and metabolic syndrome. Over the last decade, mitochondrial transplantation has emerged as a radical therapeutic paradigm for restoring metabolic competence via the exogenous delivery of intact organelles. While early evidence confirms that internalized mitochondria can rescue bioenergetic deficits and suppress apoptotic signaling, the transition to clinical practice is hindered by poor targeting specificity, low delivery kinetics, and post-isolation functional decay. This review highlights a pivotal shift toward mitochondrial engineering, where the organelle is no longer viewed as a static payload but as a programmable therapeutic unit. By integrating principles from synthetic biology, nanomedicine, and biomaterials, researchers are now modifying mitochondria to enhance their ROS-scavenging capacity, stability in the extracellular milieu, and cell-specific uptake. We critically evaluate emerging strategies for organelle modification, including surface functionalization, genetic modulation, and advanced delivery platforms like fusogenic capsules and photothermal nanoblades. Finally, we discuss the redox-dependent mechanisms underlying therapeutic efficacy and the translational hurdles essential for evolving mitochondrial engineering into a precise, scalable clinical reality.

DOI: https://doi.org/10.1016/j.redox.2026.104338

Front Immunol. 2026 ;17 1863593

Mitochondrial transfer-mediated metabolic reprogramming and drug resistance in bone metastasis: mechanisms and therapeutic strategies.

Wei Deng, Bingyu Liu, Songtao Xiang.

Bone is one of the most common sites of distant metastasis in solid tumors, particularly breast cancer, prostate cancer, and lung cancer. Bone metastatic lesions frequently exhibit persistent resistance to multiple systemic therapies, including chemotherapy, targeted therapy, endocrine therapy, and immune checkpoint inhibitors (ICIs). Accumulating evidence suggests that metabolic reprogramming within the bone microenvironment contributes to this resistance, yet the upstream mechanisms remain incompletely understood. Intercellular mitochondrial transfer has emerged as a potential link between the bone marrow niche and tumor metabolic adaptation. Bone marrow mesenchymal stem cells (BMSCs) have been reported to deliver functional mitochondria to tumor cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), and gap junctions, a process proposed to be regulated by metabolic stress, chemokine signaling (CXCL12/CXCR4), and inflammatory cues. The bone marrow microenvironment-characterized by hypoxia, high cell density, and lipid abundance-together with the intrinsic transfer capacity of BMSCs, may facilitate efficient mitochondrial delivery. Following transfer, exogenous mitochondria have been shown, largely in vitro and preclinical models, to restore oxidative phosphorylation (OXPHOS) through respiratory chain reassembly, mitochondrial DNA (mtDNA) replication, and membrane potential recovery, which may drive a metabolic shift from the Warburg phenotype toward a mixed state with enhanced fatty acid β-oxidation (FAO), glutaminolysis, and branched-chain amino acid oxidation. The resulting high adenosine triphosphate (ATP) pool and reshaped redox homeostasis have been proposed to support multiple resistance mechanisms, including ATP-dependent drug efflux, enhanced DNA damage repair, apoptosis resistance, metabolic bypass of targeted therapies, immunosuppressive nutrient competition, and cancer stem cell (CSC) maintenance with therapy-induced dormancy. Mitochondrial dynamics remodeling and metabolic-epigenetic crosstalk may further establish a "metabolic memory" sustaining the resistant phenotype. Notably, transfer patterns appear to exhibit tumor type specificity across breast cancer, prostate cancer, and lung cancer, with multiple myeloma (MM) considered here as a mechanistically informative, marrow-resident comparator rather than a parallel solid-tumor setting. Conceptually proposed therapeutic strategies targeting this axis encompass transfer blockade, OXPHOS and FAO inhibition, and bone-targeted nanodelivery systems, none of which has yet demonstrated efficacy specifically against mitochondrial transfer in patients with bone metastasis. Importantly, several controversies remain unresolved, including the durability and functional integrity of transferred mitochondria, the risk of dye-tracing artifacts, in vivo detection sensitivity, and the clinical translation of pathway-specific inhibitors. This review systematically examines the reported molecular mechanisms of mitochondrial transfer between BMSCs and tumor cells, its proposed role in OXPHOS reprogramming and drug resistance in bone metastasis, and emerging therapeutic strategies, aiming to provide a critical framework for developing metabolism-targeted interventions to overcome bone metastatic resistance.

Keywords: bone marrow mesenchymal stem cells; bone metastasis; drug resistance; metabolic reprogramming; mitochondrial transfer; oxidative phosphorylation; tumor microenvironment; tunneling nanotubes

DOI: https://doi.org/10.3389/fimmu.2026.1863593