Lung cancer’s spread to bone is one of the most destructive stages of the disease, often causing severe pain, fractures, spinal cord compression and dangerous disturbances in blood calcium levels. A new study published in Experimental & Molecular Medicine identifies a previously underappreciated cellular pathway that may help explain how the bone environment becomes more supportive of metastatic growth. The research focuses on itaconate, a small metabolic molecule produced by immune cells, and suggests that its effects can change when macrophages undergo a transformation into myofibroblast-like cells.
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.
Tags: extracellular matrix remodeling in lung cancerimmune cell reprogramming in cancerimmune-metabolic interactions in metastasisitaconate in tumor microenvironmentlung cancer bone invasion mechanismslung cancer bone metastasismacrophage-to-myofibroblast transitionmetabolic regulation of cancer spreadrole of HSPA8 in metastasissignaling pathways in macrophage transitiontumor microenvironment modulationtumor-associated fibroblasts
