'How Metastases Get a Foothold': Mitochondrial Glutathione Import Helps Breast Cancer Colonize the Lungs

Metastases require special "fuel" and signals - and a new study in Cancer Discovery shows that mitochondrial glutathione (GSH) is such a limiting resource. The researchers compared mitochondrial metabolites of primary and metastatic breast cancer cells and saw that during lung colonization, GSH accumulates in the mitochondria due to increased import via the SLC25A39 transporter. If this "import" of glutathione is turned off, the cells lose the ability to anchor in a new organ, although the growth of the primary tumor is almost unaffected. The key mediator of this effect is the ISR stress pathway with the transcription factor ATF4.

Background of the study

Metastasis is not just a “journey” for a tumor cell, but a series of bottlenecks: from detachment and migration to colonization of a new organ, where cells face hypoxia, nutrient deficiency, and immune system pressure. Growing evidence indicates that mitochondria and local metabolic resources are decisive at this point. A recent paper in Cancer Discovery has put mitochondrial glutathione (GSH) forward: its import via the SLC25A39 transporter turns out to be necessary for the survival of breast cancer metastases to the lungs and is associated with the activation of the integrated stress response (ISR) via ATF4.

Until recently, mammals had no clear “importer” of glutathione into mitochondria. In 2021–2022, several groups showed that SLC25A39 (and related SLC25A40) plays this role: loss of SLC25A39 depletes the mitochondrial, rather than the total cellular, GSH pool, disrupts the functioning of proteins with iron-sulfur clusters, and links glutathione metabolism to the respiratory chain. Later, a feedback loop was described: if mitochondrial GSH is low, SLC25A39 levels increase, helping to restore balance. These basic observations laid the groundwork for oncology applications.

In parallel, the role of ISR/ATF4 in tumor progression has been strengthened. This pathway helps cells survive stress by fine-tuning protein synthesis and metabolism; in breast cancer and other tumor models, ATF4 promotes migration, invasion, and survival of dormant cells, while suppression of the PERK-ISR pathway reduces metastasis. Moreover, activated stromal ISR can prepare a “niche” for lung metastases. Against this background, the “mitochondrial GSH → optimal ATF4 activation” link during colonization appears biologically plausible and clinically relevant.

The implications for therapy are twofold: one can try to disrupt GSH import (target of SLC25A39) or block the stress bypass at the ISR/ATF4 level - especially in the "window of vulnerability" of early colonization, when dependence on these pathways is maximal. In this case, one must take into account the systemic significance of glutathione: selectivity, timing and organotropy will be the key to translating the finding. The new article actually localizes the vulnerability precisely at the metastatic stage, almost without affecting the growth of the primary tumor - an important benchmark for future preclinical strategies.

How it was shown

The authors used a combination of 'omics' and functional tests in human and mouse models.

• Mitochondrial metabolomics: comparison of metastatic and primary cells reveals selective accumulation of GSH in mitochondria during lung colonization.
• Genetic screens: SLC25A39 knockout disrupted early colonization of lung metastases (PDX lines), while primary tumor growth remained unchanged.
• CRISPR activation screen: a bypass pathway, ATF4, has been identified that partially restores metastatic potential in SLC25A39 deficiency.
• Signal mechanics: SLC25A39 is required for optimal ATF4 activation during metastasis and hypoxia - the link between mitochondrial GSH and the integrated stress response (ISR). Bottom line: mitochondrial GSH is a necessary and limiting metabolite for metastatic progression.

Why is this important?

Glutathione is usually associated with antioxidant protection, but here it is the role in metastasis that is critical, regardless of the “classical” function of the antioxidant. The work suggests that metastases have a metabolic vulnerability specific to the colonization phase - it can be attempted to touch it without affecting the primary tumor. This expands our understanding of how mitochondria control the fate of tumor cells outside the original focus.

Where did SLC25A39 come from and what does glutathione have to do with it?

SLC25A39 is a recently identified mitochondrial GSH transporter. It was discovered as a “gateway” for glutathione into mammalian mitochondria; without this entry, cellular processes and some tissues (e.g., erythropoiesis in mice) suffer. The new paper effectively brings this basic biology into the oncologic context of metastasis.

• Fact: When SLC25A39 is increased, the mitochondrial GSH pool increases.
• In breast cancer: this pool is needed to turn on ATF4/ISR and survive the “bottleneck” of early colonization - lack of oxygen, nutrition, immune pressure.

What does this mean for therapy (hypotheses for now)

The idea is simple: prevent metastases from “importing” GSH or break their stress bypass.

• Target SLC25A39 or modulate the mitochondrial GSH pool in the early colonization window of vulnerability.
• Hit ISR/ATF4, which serves as a "bypass" when SLC25A39 is lost.
• Combine: with immunotherapy/chemotherapy to prevent cells from experiencing the stress of transplantation to new soil.

Important: systemic intervention in GSH metabolism is potentially risky - glutathione is needed by healthy tissues too. Therefore, the practical way is selective targets (transporter, "stress node") and smart timing (perimetastatic window). This is the subject of future preclinical testing and drug design.

Details that are easy to miss

• The effect is local: colonization (planting and engraftment) suffers, but the growth of the primary tumor does not. This means that we are talking about the specificity of the metastatic stage, and not universal proliferation.
• The ATF4/ISR signal is not just a "stress background" but a functional switch for survival in a new environment. Its activation is capable of bypassing the GSH import block.
• In PDX (patient-derived xenograft) models, the pattern is repeated, increasing the translational potential of the results.

Limitations (and what to check next)

• This is preclinical at this time: cultures, mice, PDX; the safety and selectivity of SLC25A39/ISR interventions in humans have not been studied.
• Tools needed: chemical inhibitors/modulators of SLC25A39, “on-target” markers of mitochondrial GSH suppression.
• It is important to understand organotropy: is GSH import equally critical for colonization of the liver, brain, bone, and not just the lungs?

Conclusion

Metastasis is a marathon with a dangerous “first kilometer.” New work shows that mitochondrial glutathione imported via SLC25A39, which unleashes the ATF4/ISR stress pathway, helps cancer cells get through it. Blocking this import or depriving the cell of a “bypass” is a potential strategy to stop metastasis in its tracks. Now the ball is in the court of chemical biologists and preclinical developers.

Source: Yeh HW et al. Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling. Cancer Discovery (online ahead of print, July 31, 2025), doi:10.1158/2159-8290.CD-24-1556.