KSRP-dependent immunogenic cell death induced by pyridazinone derivative IMB5036 drives antitumor immunity in neuroblastoma.

The small-molecule pyridazinone derivative IMB5036 (IMB) exhibits significant cytotoxicity against multiple cancer cell lines, and KH-type splicing regulatory protein (KSRP) is confirmed as its direct binding partner. However, KSRP's functional role in neuroblastoma (NB) and the mechanism mediating IMB's antitumor effects remain unclear. This study analyzed public tumor databases and found KSRP expression negatively correlates with NB patients' median survival. Experiments showed IMB induces NB cell pyroptosis, immunogenic cell death (ICD, with calreticulin exposure), and cGAS-STING activation (to boost antitumor immunity), while CRISPR-Cas9-mediated KSRP knockout notably attenuates these effects. Transcriptome sequencing further confirmed KSRP mediates IMB's regulation of HSPA6/RSAD2. This study clarifies KSRP-dependent ICD drives NB antitumor immunity, providing a basis for KSRP-targeted NB immunotherapies.