NFYB-lncRNA axis resets the tumor microenvironment to promote HCC aggressive progression by a positive feedback loop.

Metastases are a primary cause of cancer-associated mortality; however, the mechanisms underlying aggressive progression have not been clearly elucidated. Genome-wide features of chromatin accessibility through ATAC-seq from HCC primary and metastatic tumors revealed that many distal regulatory elements spreading the genome become accessible during aggressive progression, the changes of which are associated with NFY-family. And NFYB is frequently upregulated in tumor with metastasis. Mechanistically, LINC01137 recruits SMYD3 to enhance H3K4me3 occupancy at IL-1β, CXCL2 and CCL20 promoters by inhibiting lysine ubiquitination to stabilize NFYB, which in turn upregulates IL-1β, CXCL2 and CCL20. HCC-derived cytokine transforms macrophages to the M2 phenotype to foster an inhibitory tumor microenvironment and anti-PDL1 tolerance. Importantly, LINC01137 transcription is activated by the NFYB/KAT2B complex in a feed-forward loop. Notably, treatment with an IL-1β inhibitor enhances the blockade efficacy of PD-L1 in NFYB-overexpressing HCC. Our findings imply an immunosuppressive role of NFYB-LINC01137 signaling during aggressive HCC progression and support the concept of microenvironment engineering in immunotherapy.