Cutaneous Melanoma Drives Metabolic Changes in the Aged Bone Marrow Immune Microenvironment

ABSTRACT Background Melanoma is the deadliest form of skin cancer, with increasing incidence rates among the older population. The immune system experiences age‐related changes that can impact tumor progression and treatment efficacy. Additionally, aging leads to systemic non‐immune changes, such as enhanced adiposity and iron accumulation in the bone marrow (BM). Aims This study aims to investigate how age‐related alterations in the BM, alongside the presence of melanoma, influence the immune response and susceptibility to ferroptosis in aged mice. Methods and Results Utilizing an aged mouse model with melanoma, we observed significant changes in iron and lipid levels within the BM, as well as alterations in immune cell populations. Specifically, our findings indicate that tumor burden expands the myeloid compartment and contracts the lymphoid compartment in the BM niche. Aging increases neutral lipids within the BM, but tumor burden in aged mice appears to reverse this effect. We noted elevated intracellular neutral lipid levels in monocytes due to the tumor burden. Bone marrow–derived macrophages (BMDMs) from aged mice exhibited altered fatty acid synthase and fatty acid uptake protein expression. While aging leads to increased iron accumulation and lipid peroxidation in the BM, the presence of melanoma counteracts these changes. Disruptions in iron and lipid homeostasis heightened the risk of ferroptosis. Notably, imidazole ketone erastin and aging influenced intracellular ferrous iron levels and immune cell populations. Conclusion Overall, melanoma induces an age‐specific metabolic response in the BM, which may sensitize immune cells to ferroptosis inducers.