Xueru Jia, Yangyang Shi, Jianrong Su, Yibo Zhou, Wei Li, LI Ya-jun, Baoshan Di, Fangyu An, Chunlu Yan
Osteosarcoma is the most common primary malignant tumour of bone. It is highly malignant and invasive, posing a serious threat to human health. Neoadjuvant chemotherapy with cisplatin and doxorubicin combined with surgical resection is the standard treatment option, which can improve the 5-year survival rate of patients to approximately 60%. However, chemotherapy resistance, postoperative distant metastasis, and adverse reactions are key bottlenecks leading to poor prognosis, and new precision treatment strategies are urgently needed. SLC7A11, a core functional subunit of the cystine-glutamate antiporter System Xc - , is a key regulator of iron homeostasis and is closely associated with the infiltration and function of various immune cells in the tumour immune microenvironment, thereby regulating osteosarcoma progression and the antitumor immune response. Targeting SLC7A11 to synchronously regulate iron homeostasis and remodel the immune microenvironment is expected to improve osteosarcoma treatment. To systematically assess the regulatory mechanism and clinical application potential of SLC7A11, we retrieved the relevant literature from PubMed, Web of Science, Elsevier ScienceDirect, and other databases from April 2001 to July 2025. We screened and integrated high-quality studies related to SLC7A11, iron death, and the immune microenvironment of osteosarcoma. This review focuses on the role of SLC7A11 in iron death-related pathways (such as the GPX4-GSH, FSP1-CoQ10, and GCH1-BH4 pathways) and immune cells in the tumour immune microenvironment (such as TAMs, tans, and T cells), commenting on the molecular mechanisms of osteosarcoma development and summarising the regulatory effects of inhibitors targeting SLC7A11 (including small molecule compounds, active ingredients of traditional Chinese medicine, non-coding RNAs, exosomes, and nanomaterials) on osteosarcoma. The SLC7A11-targeting strategies summarised in this review provide a solid theoretical basis for clinical transformation, such as optimising combination chemotherapy regimens, developing personalised immunotherapy regimens, and constructing targeted drug delivery systems, which are expected to effectively improve the efficacy and prognosis of patients with osteosarcoma.