Macrophages are immune cells that normally detect danger, remove damaged material and coordinate inflammation. Within tumors, however, they can be reprogrammed by signals from cancer cells and surrounding tissues. The study by Qian, Tan, Wang and colleagues examines a process known as macrophage-to-myofibroblast transition, or MMT. During this transition, macrophages acquire characteristics associated with myofibroblasts—cells that produce extracellular matrix, remodel tissue and participate in wound repair. In a tumor, these activities can be redirected to build a microenvironment that favors cancer invasion and colonization.

The researchers report that MMT-derived cells produce itaconate in a way that promotes the ability of lung cancer cells to establish metastases in bone. Itaconate is generated from the tricarboxylic acid cycle, the central metabolic pathway that supplies energy and biosynthetic materials to cells. It is best known as an immunometabolite, meaning that it connects cellular metabolism with immune behavior. In many contexts, itaconate can suppress excessive inflammation and protect tissues from damage. The new findings indicate that, in the setting of lung cancer, itaconate can acquire a harmful function by supporting the biological conditions required for skeletal metastasis.

The proposed mechanism involves HSPA8, a molecular chaperone also known as heat shock cognate protein 70. HSPA8 helps newly synthesized or damaged proteins maintain their correct structure, transports selected proteins within the cell and participates in lysosomal degradation pathways. These functions make it an important regulator of cellular stress responses and protein quality control. According to the study, itaconate targets HSPA8, altering a process that ultimately strengthens the capacity of lung cancer cells to survive and grow in the bone microenvironment.

Bone is not a passive destination for metastatic cancer. It is a highly active organ in which osteoblasts build bone, osteoclasts break it down and stromal cells, immune cells and blood vessels continuously exchange signals. Tumor cells that reach bone must adapt to this specialized ecosystem. They can stimulate osteoclast activity, release factors that alter bone formation and exploit growth signals stored in the mineralized matrix. This creates a self-reinforcing cycle in which bone destruction releases molecules that further support tumor expansion. By linking MMT-derived itaconate to HSPA8, the study adds a metabolic and protein-regulatory layer to this complex process.

The research also emphasizes how cells surrounding a tumor can influence the behavior of cancer cells without becoming malignant themselves. Macrophages that transition toward a myofibroblast-like state may contribute to the formation of a fibrotic, mechanically altered and chemically supportive niche. Their secreted molecules and remodeled extracellular matrix can affect cancer-cell movement, resistance to stress and communication with bone cells. Itaconate appears to function as one of the signals connecting these altered stromal cells with metastatic tumor cells. This finding reinforces the view that metastasis is not driven solely by mutations inside cancer cells, but also by interactions between malignant cells and their tissue environment.

HSPA8 may be particularly important because metastatic cells encounter substantial stress while traveling through the circulation and adapting to a new organ. They must withstand changes in oxygen availability, nutrient supply, mechanical forces and immune surveillance. A more active protein quality-control system could help them maintain essential proteins and avoid cell death. If itaconate modifies HSPA8-dependent processes, the metabolite may give cancer cells a survival advantage during the early stages of bone colonization. The study therefore points to HSPA8 as a possible molecular bridge between metabolic signals from the tumor microenvironment and the stress tolerance of metastatic cells.

The findings could eventually inform therapeutic strategies, although they do not yet establish a treatment for patients. One possible approach would be to interfere with the formation or activity of MMT-derived myofibroblast-like cells. Another would be to reduce pathological itaconate production or block its interaction with HSPA8. Targeting these pathways would require considerable caution because macrophages, itaconate and HSPA8 all perform essential functions in normal immunity, tissue repair and cellular maintenance. A therapy that suppresses them too broadly could impair host defense or damage healthy organs. Future work will need to determine precisely how itaconate modifies HSPA8, which molecular partners are involved and whether the pathway operates similarly in different forms of lung cancer.

The study also raises questions about when this pathway becomes active. It may influence the preparation of distant tissues before cancer cells arrive, a process often described as formation of a pre-metastatic niche. Alternatively, it may act mainly after tumor cells have seeded the bone, helping them remain viable and expand. Distinguishing these stages will be important for treatment design. Preventing the establishment of metastases could require a different intervention from controlling established bone lesions, which are often protected by dense stromal networks and resistant to conventional therapies.

By revealing a connection between macrophage plasticity, immunometabolism and protein homeostasis, the work broadens the scientific picture of lung cancer bone metastasis. Itaconate is no longer viewed only as a by-product of immune-cell metabolism; in this context, it becomes a signal capable of reshaping tumor behavior through HSPA8. The results highlight the importance of studying cancer as an ecosystem in which immune cells, connective-tissue cells, metabolites and malignant cells continuously influence one another. If validated in additional models and patient samples, the MMT–itaconate–HSPA8 pathway could become a valuable framework for understanding why lung cancer so often spreads to bone and for developing more precise ways to disrupt that process.

Subject of Research: Macrophage-to-myofibroblast transition-derived itaconate and its role in promoting bone metastasis in lung cancer through HSPA8.

Article Title: Macrophage-to-myofibroblast transition-derived itaconate promotes bone metastasis in lung cancer through targeting of HSPA8.

Article References: Qian, J., Tan, Z., Wang, J. et al. Macrophage-to-myofibroblast transition-derived itaconate promotes bone metastasis in lung cancer through targeting of HSPA8. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01799-9

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01799-9

Keywords: Lung cancer; bone metastasis; macrophages; myofibroblasts; macrophage-to-myofibroblast transition; itaconate; HSPA8; tumor microenvironment; immunometabolism; cancer metastasis.

Mitochondria are crucial intracellular structures responsible for generating adenosine triphosphate (ATP), the primary energy currency in biological systems. The ability of skin cancer cells to shuttle mitochondria into fibroblasts is facilitated by microscopic, membrane-bound tubes that form physical conduits between the cells. These nanoscopic tubes bear a striking functional resemblance to pneumatic tube systems once used to transport physical objects between locations. Such direct mitochondrial transfer represents a fascinating example of intercellular communication hijacked by malignant cells to manipulate their environment favorably.

Upon receiving mitochondria from cancer cells, the fibroblasts undergo a remarkable functional transformation into what are termed tumor-associated fibroblasts (TAFs). These reprogrammed fibroblasts demonstrate increased proliferation rates and enhanced production of ATP, thereby amplifying the metabolic support they provide to the tumor. Moreover, TAFs secrete an elevated level of growth factors and cytokines—signaling molecules that orchestrate cellular activities—fostering a microenvironment conducive to aggressive tumor expansion and invasiveness.

Beyond metabolic and proliferative changes, these hijacked fibroblasts also profoundly alter the extracellular matrix (ECM), the intricate network of proteins and glycoproteins that provide structural support to tissues. By modulating ECM composition, these tumor-associated fibroblasts create a mechanical and biochemical niche that promotes cancer cell survival, invasion, and intercellular communication. This remodeling of the ECM underlines the multifaceted role of fibroblasts not only in tissue homeostasis but also in the dynamic progression of malignancies.

The serendipitous nature of this discovery came to light when postdoctoral researcher Michael Cangkrama observed slender tube-like structures bridging cancer cells and fibroblasts in controlled co-culture environments. These nano-bridges served as channels for mitochondrial passage, a phenomenon previously unexplored in the context of cancer-to-stroma interaction. While mitochondrial transfer between cells has been documented in other physiological contexts—such as neuronal rescue following ischemic stroke—this finding marks a paradigm shift by demonstrating how cancer cells exploit a natural intercellular salvage pathway to their advantage.

Notably, while it has been recognized that stromal cells can transfer mitochondria to tumor cells enhancing tumor fitness, the demonstration of mitochondria transfer in the reverse direction—from cancer cells to fibroblasts—is unprecedented. This bi-directional exchange elucidates a complex crosstalk within the tumor microenvironment, whereby cellular communication and organelle trafficking synergize to bolster tumor growth and resilience.

Further studies at ETH Zurich established that this mitochondrial transfer phenomenon is not exclusive to skin cancer. Evidence now indicates its presence in other malignancies characterized by dense stromal components, such as breast and pancreatic cancers. The latter is especially significant given the notoriously fibrotic nature of pancreatic tumors, where abundant fibroblasts heavily influence disease progression and therapy resistance.

Deciphering the molecular underpinnings of mitochondrial transfer, Werner’s team identified the protein MIRO2 as a key facilitator in this process. MIRO2, known for its role in mitochondrial trafficking within neurons, is highly expressed in cancer cells actively transferring mitochondria. Its presence was particularly concentrated at the invasive fronts of tumors, precisely where cancer cells interact most intimately with the surrounding stroma, including fibroblasts.

Using clinical tissue samples, researchers localized MIRO2 expression to tumor cells at the margins infiltrating connective tissue, corroborating its functional significance in vivo. This localization suggests that MIRO2-mediated mitochondrial transfer is a critical mechanism that tumors leverage during invasion and metastasis. Importantly, inhibiting MIRO2 expression or function effectively blocked mitochondrial transfer in both laboratory cell cultures and preclinical mouse models, preventing fibroblast reprogramming and dampening tumor-supportive activities.

These findings open promising avenues for therapeutic intervention. Targeting MIRO2 to disrupt mitochondrial transfer could impair the tumor’s ability to reprogram its microenvironment, thereby stalling progression and metastasis. However, the transition from laboratory models to human applications remains a formidable challenge. Potential MIRO2 inhibitors will require rigorous development to ensure specificity, minimal side effects, and clinical efficacy.

While the timeline for clinical translation remains uncertain, this discovery sets the stage for innovative cancer treatments centered around disrupting the metabolic and cellular dialogue between tumor cells and their stroma. Through such interventions, it may become possible to curtail tumor growth by dismantling the support systems that cancer cells covertly establish within their microenvironment.

As cancer research advances, understanding and intercepting intercellular interactions such as mitochondrial transfer will be critical for developing next-generation therapies. The ETH Zurich team’s work is a testament to how fundamental cellular mechanisms, once uncovered, can reveal hidden vulnerabilities in the seemingly invincible nature of malignant tumors.

Subject of Research:
Mitochondrial transfer from cancer cells to fibroblasts and its role in tumor progression.

Article Title:
MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.

News Publication Date:
28-August-2025

Web References:
https://doi.org/10.1038/s43018-025-01038-6

References:
Cangkrama M, Liu H, Wu X, et al. MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer. 28 August 2025. DOI: 10.1038/s43018-025-01038-6

Image Credits:
Michael Cangkrama / ETH Zurich / BioRender

Keywords:
Mitochondrial transfer, cancer-associated fibroblasts, tumor microenvironment, MIRO2 protein, skin cancer, intercellular communication, extracellular matrix remodeling, tumor progression, mitochondrial trafficking, stromal reprogramming, therapeutic targeting, cancer metabolism