Tumor cells steal immune mitochondria to aid lymph node spread - medicalxpress

Graphical abstract. Credit: Cell Metabolism (2026). DOI: 10.1016/j.cmet.2025.12.014

Stanford University-led researchers report that tumor cells hijack mitochondria from immune cells, reducing anti-tumor immune function and activating cGAS-STING and type I interferon signaling that promotes lymph node metastasis.

Lymph nodes hold dense networks of immune cells and can become a site of tumor colonization. Mechanisms that let tumor cells subvert tumor-immune microenvironments to favor spread to lymph nodes remain incompletely understood.

Mitochondrial transfer, the movement of mitochondria between cells, is a mode of intercellular communication that reshapes metabolism, stress responses, and cellular function across diverse physiological and pathological settings. Recruiting outside mitochondria into cancer cells can enhance oxidative phosphorylation, promote survival under metabolic stress, and influence therapy resistance.

Uncertainty remains around whether mitochondrial transfer from distinct cell types elicits unique features and clinical behaviors in cancer cells. The consequences of mitochondrial transfer and any impact on tumor dissemination have been poorly characterized.

Lymph node metastasis is a critical early step in cancer progression that can create a systemic impairment of tumor control. Mechanisms by which tumor cells subvert early immune surveillance in lymph nodes are also incompletely understood.

Previous reports have found that T cells and macrophages can transfer mitochondria to cancer cells. The extent of mitochondrial transfer by other immune cells remains unclear, along with any connections to lymph node colonization.

In the study, "Mitochondrial transfer from immune to tumor cells enables lymph node metastasis," published in Cell Metabolism, researchers tracked mitochondrial movement from immune cells into tumor cells and tested whether that transfer links immune impairment with lymph node metastasis through cGAS-STING and type I interferon signaling.

Experiments set out to address uncertainty around how tumor cells subvert tumor-immune microenvironments to favor spread to lymph nodes, while also probing whether mitochondria arriving from immune cells carry consequences beyond metabolic support.

Flow cytometry and confocal microscopy tracked mitochondria movement into tumor cells after implantation of tagged colon, breast, and melanoma cancer cells into mitochondria reporter MtD2 mice.

Researchers tagged colon, breast, and melanoma cancer cells so donor mitochondria could be detected inside tumor cells. Mouse experiments paired those tagged cancer cells with mice carrying a mitochondria reporter signal, allowing host mitochondria to be seen inside cancer cells at tumor sites and in draining lymph nodes.

Bone marrow transplantation created chimeric mice where the mitochondria reporter signal stayed within immune cells, tightening donor identity to hematopoietic compartments. Genetic differences in mitochondrial DNA between mouse strains provided a second way to detect donor mitochondrial material inside tumors.

Co-culture experiments placed tumor cells and immune cells together to watch transfer during direct contact and to test conditions that altered transfer rates, including low oxygen and inflammatory stimulation. Disruption of physical contact and of cell-to-cell transfer structures tested dependence on direct interaction.

Immune donor cells were separated into groups that retained mitochondria or lost mitochondria during contact with tumor cells, followed by readouts tied to antigen presentation and cytotoxic function.

Tumor cells that received mitochondria were compared with tumor cells that did not for immune-evasion markers and for gene expression patterns linked to type I interferon signaling and cytosolic DNA sensing.

Mitochondria caught crossing into tumor cells

Tumor cells acquired mitochondria from host cells across colon, breast, and melanoma models. Immune cells were identified as a donor source in bone marrow chimera experiments that restricted the reporter signal to hematopoietic cells. Draining lymph nodes carried a higher fraction of tumor cells with immune-derived mitochondria than primary tumors.

Direct physical contact supported transfer, with higher transfer under hypoxic stress and inflammatory cues. Disruption of transfer structures and knockdown of a transfer-related factor reduced transfer, paired with reduced lymph node metastasis incidence in reported mouse experiments. mtDNA polymorphism tracing added a second line of evidence that donor mitochondrial DNA could be detected in tumor material.

Immune weakening meets tumor escape programs

Immune cells that lost mitochondria showed reduced antigen-presentation and co-stimulatory machinery, with reduced activation and cytotoxic capacity reported for natural killer and CD8 T cells. Changes aligned with impaired immune surveillance in the co-culture systems described.

Tumor cells that received immune-derived mitochondria showed features linked to lymph node metastasis, including increased immune-evasion marker expression and activation of type I interferon pathways tied to cGAS-STING signaling.

Mitochondrial fusion and mtDNA leakage into the cytosol linked mitochondrial transfer to cGAS-STING activation. Inhibition of mitochondrial transfer machinery or inhibition of cGAS, STING, or type I interferon reduced lymph node metastasis in experiments.

Analyses of human datasets associated higher mitochondrial transfer signatures with lymph node metastasis and cGAS-STING pathway activation. Receiver prediction was limited when mitochondrial coverage was low and cell numbers were small.

Targets along the transfer chain

Authors identify immune-to-tumor cell mitochondrial transfer as a central mechanism that facilitates lymph node colonization through two coordinated effects. Loss of mitochondria disables anti-tumor immunity by diminishing antigen presentation and impairing cytotoxic function across multiple immune lineages, while immune-derived mitochondria activate the cGAS-STING pathway in tumor cells and induce a type I interferon program that promotes immune evasion and lymph node colonization.

Targeting mitochondrial transfer or the resulting cGAS-STING signaling represents a promising strategy to restrict lymph node metastasis, a critical early step in systemic cancer progression. 

by Justin Jackson, Medical Xpress

edited by Sadie Harley, reviewed by Robert Egan 

Source: Tumor cells steal immune mitochondria to aid lymph node spread