Nelfinavir (NFR), originally developed as an antiretroviral agent for the human immunodeficiency virus, has demonstrated anti-cancer properties across various malignancies; however, its therapeutic potential in Glioblastoma (GBM) remains largely unexplored. In the present study, we investigated the anti-tumor effects of NFR in GBM using a comprehensive panel of experimental models, including established GBM cell lines, GBM cell line-derived spheroids, patient-derived primary glioma cells, and patient-derived glioma organoids. We further evaluated the anti-tumor potential of NFR in combination with standard chemotherapeutic agents, carboplatin and doxorubicin, across these platforms. In vitro analyses revealed that NFR significantly inhibits GBM cell proliferation and induces both apoptotic and necrotic cell death. Additionally, we identified that NFR treatment is associated with activation of the AIM2 inflammasome in GBM cells and may contribute to NFR-induced anti-glioma effects. However, activation of the AIM2 inflammasome alone is not essential to induce its anti-tumor effects in GBM. Collectively, our findings highlight NFR as a promising therapeutic candidate for GBM, exerting its effects through anti-proliferative and pro-death mechanisms.
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