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

  • FEBS Lett. 2026 May 26. doi: 10.1002/1873-3468.70364.
Yanqun Dong  1  2  3 ,  Yanfeng Xu  4 ,  Junyi Zhang  1 ,  Hanyu Hong  1 ,  Lingli Gao  1 ,  Hanrui Wei  1 ,  Yijia Zheng  1 ,  Xing Lv  1 ,  Yan-Bo Zheng  1 ,  Jigang Yang  4 ,  Jian-Hua Gong  1
Affiliations
  • 1. Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2. Institute of Materia Medical, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3. Research Unit of Cell Growth Factors and Diseases for Research and Clinical Translation, Chinese Academy of Medical Sciences & Peking Union Medical College, Wenzhou, China.
  • 4. Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, China.
PMID: 42186376 DOI: 10.1002/1873-3468.70364
Abstract

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.

Keywords
IMB5036; KSRP; antitumor immunity; immunogenicity cell death; neuroblastoma.
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