Chunchao Zhang

High-risk (HR) neuroblastoma (NB) remains a leading cause of pediatric cancer mortality, frequently driven by MYCN amplification or MYC overexpression. Despite their central role, direct pharmacological targeting of these transcription factors remains clinically challenging. Here, we identify CaM kinase–like vesicle-associated protein (CAMKV) as a MYCN/MYC-regulated effector of NB pathogenesis. Although previously classified as a nonfunctional pseudokinase, we demonstrate that CAMKV possesses intrinsic kinase activity that is essential for tumor growth. Analysis of patient datasets and primary tumors shows that elevated CAMKV expression correlates with advanced disease stage and poor overall survival. Through integrated transcriptomics, ChIP-seq, and phosphoproteomics, we establish CAMKV as a central signaling hub that coordinates metabolic and proliferative pathways. Both genetic depletion and small-molecule inhibition of CAMKV significantly impair NB cell proliferation in vitro and suppress tumor growth in vivo. Collectively, our findings establish CAMKV as a unifying therapeutic vulnerability and highlight this functional kinase as a promising target for translational development in HR NB.

Supplemental Figure S14. PRDM1 KD cells undergo less apoptosis than scr control cells after six cycles of tumor challenge.

Supplemental Figure S1. Titration of lentiviral vector to identify viral volume for gRNA library transduction.

Supplemental Figure S8. PRDM1 KO and B2M KO GD2.CAR NKTs demonstrate similar levels of cytotoxic activity and granzyme B production after one round of tumor challenge.

Supplemental Figure S19. Gating strategy to measure iNKT cell frequency in liver or spleen on mouse experiment described in Figure 5D.

Supplemental Figure S15. GD2.CAR NKTs and scr control GD2.CAR NKTs have similar gene expression profiles after one and six cycles of tumor challenge.

Supplemental Figure S13. GD2.CAR NKTs with PRDM1 KD express lower levels of TIGIT and CD39 than scrambled control cells after six cycles of tumor challenge.

Supplemental Figure S9. Weekly bioluminescence imaging of NB tumor growth described in Figure 2J.

Supplemental Figure S3. PRDM1 and B2M gene knockout efficiency before and after serial tumor challenge.

Supplemental Figure S12. BLIMP1 levels in PRDM1 KD GD2.CAR NKTs prior to and after multiple rounds of tumor challenge.