Gliomas are the most common type of primary intracranial tumors. ConclusionsĪltogether, these findings suggest S4 as a novel ICD inducer in glioma and might have implications for S4-based immunotherapy. In glioma xenografts, S4 significantly reduced tumor growth. Furthermore, pharmacological inhibition of PERK significantly suppressed S4-triggered ICD markers and autophagy. Both PERK-eIF2α and IRE1α- XBP1 axes were activated in S4-treated cells. RNA-seq analysis indicated that the ER stress pathway was deregulated upon exposure to S4.

Inhibition of either apoptosis or autophagy significantly reversed S4-induced release of DAMP molecules. Moreover, S4 triggered CRT exposure and the release of HMGB1 and HSP70/90. S4 significantly decreased the viability of glioma cells and induced apoptosis and autophagy. Immunohistochemistry (IHC) was performed to stain Ki67 and CRT. In vivo effects of S4 were evaluated in glioma xenografts.

Pharmacological inhibition of apoptosis, autophagy, necroptosis and endoplasmic reticulum (ER) stress was achieved by inhibitors. RNA-seq was performed to compare gene expression profiles between S4-treated and control cells. The supernatants of S4-treated cells were concentrated for the determination of HMGB1and HSP70/90 expression by immunoblotting. Surface-exposed calreticulin (CRT) was inspected by confocal imaging. Glioma cell apoptosis was determined by flow cytometry. The effects of S4 on glioma cell growth were evaluated using the CCK-8, clonogenic and sphere assays. The aim of this work was to analyze whether the carbonic anhydrase IX inhibitor S4 can elicit ICD in glioma cells. Immunogenic cell death (ICD), which releases danger-associated molecular patterns (DAMP) that induce potent anticancer immune response, has emerged as a key component of therapy-induced anti-tumor immunity.

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