Hypoxic-immune axis orchestrates metastatic dissemination via HIF isoform imbalance in pancreatic neuroendocrine tumors.

Metastatic dissemination underpins mortality in pancreatic neuroendocrine tumors (PNETs), where the hypoxic, immunosuppressive microenvironment facilitates progression. Non-genetic determinants, including hypoxia-inducible factor (HIF) isoforms, preceding metastatic traits can disrupt immune homeostasis and promote aggression. However, the dynamics of HIF-immune crosstalk in PNET metastasis remain elusive. Using multi-omics and organoid models of KRAS-mutated PNETs, we uncovered rapid HIF isoform shifts, with HIF-1α/β overexpression and HIF-2α suppression emerging as pivotal. This imbalance is pronounced in advanced and metastatic PNETs. The hypoxic-immune axis is swiftly activated under pseudohypoxia and sustains in disseminated cells. It fuels immune evasion and invasion by enriching immunosuppressive cells and altering checkpoint signaling, interacting with KRAS-driven succinate accumulation. We propose that HIF isoform imbalance arises early in PNET evolution and orchestrates metastatic dissemination.