NF-κB signaling and the tumor microenvironment in osteosarcoma: implications for immune evasion and therapeutic resistance

Abstract

Osteosarcoma, a highly aggressive malignancy with a generally poor prognosis, is characterized by tumor cells' ability to evade immune responses and resist treatment. The nuclear transcription factor NF-κB signaling pathway is crucial in regulating inflammatory and immune reactions. It occupies a central position in the development of the osteosarcoma tumor microenvironment. This research aimed to explore how NF-κB influences the recruitment and polarization of tumor-associated macrophages and myeloid-derived suppressor cells, both of which contribute to immunosuppression. Furthermore, NF-κB facilitates immune surveillance evasion in osteosarcoma cells by altering the expression of immune checkpoint molecules, such as PD-L1. It also enhances tumor cell resistance to chemotherapy and radiotherapy by activating anti-apoptotic signaling pathways and exacerbating treatment-induced inflammation. Potential therapeutic approaches include using NF-κB inhibitors, possibly in combination with immune checkpoint inhibitors, to overcome tumor cell resistance mechanisms and reshape antitumor immune responses. A thorough examination of NF-κB's role in osteosarcoma development is expected to yield novel clinical treatment strategies, and significantly improve patient prognosis by targeting this key signaling pathway.

Keywords: NF-κB signaling; immune evasion and; malignant bone tumor; osteosarcoma; tumor microenvironment.

Figure 1

The two NF-κB signaling pathways include the classical (canonical) and alternative (noncanonical) routes. The classical NF-κB signaling pathway is activated by factors such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and Toll-like receptor ligands including lipopolysaccharide (LPS), as well as through the activation of T cell and B cell receptors. This pathway plays a critical role in regulating gene expression associated with inflammation, cell proliferation, survival, epithelial-to-mesenchymal transition, invasion, angiogenesis, and metastasis. However, the alternative NF-κB signaling pathway is initiated by molecules such as lymphotoxin (LT), receptor activator of NF-κB ligand (RANKL), CD40 ligand (CD40L), and B cell-activating factor (BAFF). It primarily induces genes essential for the formation and maintenance of secondary lymphoid structures and associated components within the tumor microenvironment (TME). While LPS can also stimulate the alternative pathway to a lesser extent, LT, RANKL, CD40L, and BAFF retain the classical pathway activation capacity as well.

Figure 2

The initial activation of Nuclear factor-κB (NF-κB) in immune cells occurs through tumor necrosis factor (TNF), interleukin-1 (IL-1), and various pathogen-associated or damage-associated molecular patterns. This activation leads to the secretion of pro-inflammatory cytokines, chemokines, and growth factors, including TNF, IL-1, IL-6, and vascular endothelial growth factor (VEGF). These pro-inflammatory signals further stimulate NF-κB and signal transducer and activator of transcription 3 (STAT3) in both cancer cells and components of the TME, enhancing cancer cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), invasion, angiogenesis, and metastasis. Additionally, cancer cells produce chemokines that attract additional immune cells to the tumor microenvironment, thereby sustaining local inflammation and establishing a chronic feedback loop that fosters continuous tumor growth and metastasis.