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

## TL;DR

This study shows how imbalances in HIF proteins, driven by KRAS mutations, create an immunosuppressive environment that promotes metastasis in pancreatic neuroendocrine tumors.

## Contribution

The study reveals a novel hypoxic-immune axis driven by HIF isoform imbalance in PNET metastasis.

## Key findings

- KRASG12C mutations cause HIF-1α/β overexpression and HIF-2α suppression in PNETs.
- HIF isoform imbalance promotes immune evasion and metastatic dissemination.
- Targeting HIF-1α reduces metastatic potential and reverses immune evasion.

## Abstract

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.

•KRASG12C mutations drive HIF-1α/β upregulation and HIF-2α suppression in PNETs•HIF isoform imbalance fosters an immunosuppressive tumor microenvironment•Structural modeling reveals covalent binding between HIF-1α and mutant KRASG12C•Targeting HIF-1α reverses immune evasion and reduces metastatic potential

KRASG12C mutations drive HIF-1α/β upregulation and HIF-2α suppression in PNETs

HIF isoform imbalance fosters an immunosuppressive tumor microenvironment

Structural modeling reveals covalent binding between HIF-1α and mutant KRASG12C

Targeting HIF-1α reverses immune evasion and reduces metastatic potential

Molecular biology; Cell biology; Cancer