IGF2BP1 in 17q-gain cooperates with MYCN to regulate purine biosynthesis and immunotherapy efficacy in neuroblastoma

However, how these genetic alterations synergize to promote tumor progression and whether their cooperation confers therapeutic vulnerabilities remain elusive. We herein performed a CRISPR-based functional screen targeting 17q-gain genes and identified the RNA m6A reader IGF2BP1 as a critical MYCN collaborator to promote aggressive neuroblastomas via activation of PAICS, a key enzyme involved in de novo purine biosynthesis.

Rewiring of PAICS-mediated nucleotide metabolism enabled tumor cells to sustain necessary purine pools for productive transcription of replicative stress-responsive genes, including CHK1, to cope with the exacerbated replication stress. Pharmacological inhibition of CHK1 elicited a robust immune reprogramming, leading to activation of cGAS-STING signaling, upregulation of MHC-I expression and synergistic tumor suppression with immune checkpoint blockade.