A research team led by Professor Yi Sun from Zhejiang University revealed a critical regulatory link between UBE2M, mitophagy and the cGAS-STING innate immune pathway in Kras^G12D driven non-small cell lung cancer (NSCLC).

Kras^G12D mutation occurs in around 15% of human NSCLC and represents an intractable clinical hurdle, while the in vivo physiological function of UBE2M during Kras-initiated lung tumorigenesis remains largely undefined.

The team generated multiple conditional knockout mouse strains with simultaneous UBE2M deletion and Kras^G12D activation selectively in lung epithelial or myeloid cells.

While UBE2M deletion did not cause any observable lung injury, simultaneous UBE2M deletion and Kras^G12D activation caused severe inflammatory TME, evidenced by pulmonary edoema, extensive immune cell infiltration and drastically shortened life-span.

Both alveolar epithelial cells and myeloid immune cells contribute to the aggravated inflammatory TME.

Mechanistic studies revealed that UBE2M protein Parkin neddylation.

UBE2M knockout inhibits Parkin activity and blocks the completion of mitophagy flux.

Coupled with enhanced mitochondrial biogenesis by Kras^G12D, damaged mitochondria accumulate and mitochondrial DNAs (mtDNAs) are released into the cytoplasm to trigger the activation of the cGAS-STING-NF-κB cascade, inceasing secretion of pro-inflammatory cytokines and recruiting various immune cells and fibroblasts to construct a inflammatory tumour microenvironment.

Series rescue experiments showed that STING antagonist H-151 markedly alleviates lung edoema, infiltrations of immune cells and proliferation of tumour cells, whereas PD-L1 immune checkpoint antibody has effect, highly indicatting that this inflammation pathology is primarily governed by the innate cGAS-STING signalling rather than adaptive immune checkpoint pathways.

The CSF-1R inhibitor GW2580 partially mitigates inflammatory lesions, revealing macrophages as key effector cells remodelling the TME.

For clinical relevance, the team analysed TCGA transcriptomic profiles of KRAS mutant human lung adenocarcinoma.

Tumour samples with low UBE2M expression display significantly higher levels of infiltrated macrophages, CD4⁺ T cells, CD8⁺ T cells and regulatory T cells, consistent with phenotypes observed in mouse models.

Collectively, this study demonstrated an unexpected protactive role of UBE2M in Kras^G12D induced lung cancer, and post a cautious note that therapeutic inhibidtion of UBE2M may provoke sustained pulmonary inflammation to accelerate tumour growth in lung cancer carrying KRAS mutations.

Source: Science China Press