Decoding the function of cancer-associated fibroblasts in osteosarcoma: Molecular pathways, therapeutic approaches and prognostic significance

Herein, we summarize the latest insights into osteosarcoma, the most prevalent primary malignant bone tumor, known for its aggressive nature, poor outcome, and especially poor prognosis when metastasis develops. Given recent research implicating the crucial role of the tumor microenvironment (TME) in osteosarcoma progression, cancer-associated fibroblasts (CAFs) emerged as key players. Through the secretion of cytokines, remodeling of the extracellular matrix (ECM), and cross-talk with osteosarcoma cells, CAFs collectively promote tumor growth, metastasis, and immune evasion. Exosomes derived from CAFs, which could also serve as important mediators of osteosarcoma progression, have been found to transport oncogenic lncRNAs like SNHG17 and linc00881. Moreover, some subtypes of CAFs, such as TOP2A + CAFs, have shown significant prognostic value for tumor aggressiveness. Thus, targeted CAFs was identified as a promising therapeutic modality, with strategies such as fibroblast activation protein (FAP) inhibition, TGF-β blockade, and CXCL12/CXCR4 axis inhibition demonstrating positive outcomes in preclinical models. The combination of CAF-targeted therapies with immunotherapies or chemotherapy has shown additional potential to reverse this CAF-induced resistance. Autophagy regulation in CAFs can be therapeutic opportunities for novel Interevent strategies.