Neddylation E2 enzyme UBE2M inhibits inflammatory lung tumor microenvironment by blocking the cGAS-STING signal upon KrasG12D activation.

UBE2M, also known as UBC12, is one of two neddylation conjugation enzymes. The in vitro cell culture work showed that UBE2M is essential for the growth and survival of cancer cells, but its in vivo role in tumorigenesis, particularly in the tumor microenvironment (TME), remains elusive. Here, we report that in a well-established KrasG12D lung tumor mouse model, Ube2m deletion caused an inflammatory TME, severe lung edema, and early death. Mechanistically, while KrasG12D activates MAPK and mTORC1 signals for proliferation, Ube2m deletion increases mitochondrial MOMP/mPTP and inhibits Parkin neddylation and activity, leading to compromised mitophagy. The combination of KrasG12D activation and Ube2m deletion caused cytoplasmic release of damaged mitochondrial DNA to activate the cGAS-STING-NF-κB pathway, followed by inflammatory cytokine secretion, immune cell infiltration, and inflammatory TME. This process is largely blocked by the STING antagonist H-151, indicating a causal role of the cGAS-STING axis. In human lung cancer with KRAS mutations, low UBE2M expression is correlated with high infiltrations of immune cells, demonstrating its relevance to human disease. Our study unexpectedly showed a paracrine role of Ube2m in the prevention of TME upon KrasG12D activation in the lung.