Role of Lactoferrin in Shaping Inflammatory Crosstalk Between Glioblastoma Cells and Tumor-Associated Astrocytes

Glioblastoma cells sustain tumor growth by releasing inflammatory cytokines that modulate the tumor microenvironment (TME). Targeting the cytokine expression profile of glioblastoma multiforme (GBM) and tumor-supportive cells represents a promising therapeutic strategy. Lactoferrin, a natural compound with recognized anticancer properties, has been poorly investigated regarding its role in modulating GBM cytokine profiles and TME cellular activity. This study evaluated lactoferrin’s ability to modulate GBM inflammatory signaling and pro-tumorigenic functions of tumor-associated astrocytes. U87MG glioblastoma cells were treated with human lactoferrin (10 μg/mL) for 72 h, and DI-TNC1 astrocytes were exposed to conditioned medium from treated and untreated U87MG cells for 24 h. Results demonstrate that lactoferrin inhibits GBM cell proliferation, migration, and stemness-related pathways while modulating inflammatory profiles through NF-κB pathway interference, downregulating pro-tumorigenic cytokines IL-6, IL-1β, IL-4, and IL-10. Increased TGF-β expression in lactoferrin-treated cells likely reflects a compensatory mechanism rather than enhanced malignancy. Furthermore, lactoferrin attenuates pro-tumorigenic effects of tumor-associated astrocytes by reducing NF-κB activation and expression of TGF-β, TNF-α, IL-4, and IL-10. This innovative study provides evidence supporting non-cytotoxic approaches targeting GBM-TME interactions, highlighting lactoferrin’s potential to attenuate glioblastoma malignancy and astrocyte inflammatory signaling, suggesting its therapeutic potential for GBM treatment.