Caerin 1.1 and 1.9 inhibit glioblastoma growth by modulating ARHGAP26-β-catenin and boosting CD8+ T cells.

Glioblastoma (GBM) is the most aggressive and lethal brain tumor, characterized by limited effective treatment options and a dismal prognosis. Current therapies often face challenges like systemic toxicity, therapeutic resistance, and an immunosuppressive tumor microenvironment. There is an urgent need for novel approaches that can both directly inhibit tumor growth and modulate the immune response. Host defense peptides, such as caerins, are emerging as promising candidates due to their inherent anti-tumor and immunomodulatory properties, offering a potential dual-action strategy to overcome the limitations of existing GBM treatments.

In vitro, U87 glioblastoma cells were treated with Caerin 1.1 (F1) and Caerin 1.9 (F3) to evaluate their impact on proliferation and key signaling pathways, including ARHGAP26, β-catenin, MMP2, MMP7, and VEGFA. Cell death mechanisms, specifically apoptosis and pyroptosis, were also assessed. In vivo, immunodeficient NSG mice and PBMC-humanized NSG mice were implanted with U87 tumors. These mice received F1/F3 treatment, and researchers monitored tumor growth, macrophage infiltration, M1-like polarization, CD8+ T cell infiltration, and PD-L1 expression within the tumor microenvironment.

Caerin 1.1 and 1.9 treatment effectively inhibited the proliferation of U87 glioblastoma cells in vitro. This inhibition was associated with increased expression of ARHGAP26 and a significant suppression of the β-catenin signaling pathway, leading to reduced expression of downstream targets such as MMP2, MMP7, and VEGFA. Cell death was primarily induced through apoptosis-related pathways, with pyroptosis-related and PI3K-related signaling showing more limited alterations. In immunodeficient NSG mice, F1/F3 altered the tumor immune microenvironment by promoting macrophage infiltration and M1-like polarization, but did not significantly inhibit tumor growth. However, a crucial difference was observed in immune-competent models:

In PBMC-humanized NSG mice, Caerin 1.1/1.9 significantly suppressed U87 tumor growth, and this effect was strongly associated with increased infiltration of macrophages and CD8+ T cells, alongside reduced PD-L1 expression. These findings demonstrate that caerins exert both direct anti-tumor effects and potent immune-modulatory activities in glioblastoma models.