Abstract

Purpose To investigate whether the combination of KPT-8602 and interferon-γ (IFN-γ) can inhibit the progression of primary central nervous system lymphoma (PCNSL) by activating ZBP1-mediated PANoptosis. Methods Human lymphoma cell lines including Raji (Burkitt's lymphoma) and U-2932 (Diffuse large B-cell lymphoma, DLBCL) were employed. The synergistic induction of PANoptosis by KPT-8602 and IFN-γ was evaluated using CCK8 assay, flow cytometry, YO-PRO/PI staining, and Western blot analysis. A mouse model of PCNSL was established through stereotaxic brain implantation. The efficacy and molecular mechanisms of the combined therapy were evaluated using HE staining, TUNEL staining, ELISA, multiplex immunofluorescence, and Western blot analysis. Results The combination therapy of KPT-8602 and IFN-γ exhibited synergistic inhibitory effects on lymphoma cell growth (CI < 1). The combination therapy group significantly enhanced apoptosis and PANoptosis, as well as upregulated the mRNA levels of PANoptosis-related inflammatory factors (IL-18, IL-1β) and the expression of PANoptosis-associated proteins. In the nude mouse model, the tumor volume was significantly smaller in the combination therapy group compared to the single-drug group. Additionally, there was a notable increase of TUNEL staining positivity in tumor tissue and elevated levels of the inflammatory factors IL-6 and CXCL13 in the cerebrospinal fluid. The Western blot analysis of tumor tissue was consistent with in vitro experiments, demonstrating significant activation of the PANoptosis pathway. Conclusions The combination of KPT-8602 and IFN-γ can activate the pan-apoptotic pathway by upregulating ZBP1, thereby effectively inhibiting the growth of PCNSL. This study presented a promising new combination treatment strategy for PCNSL.