Dynamic reprogramming and A-to-I RNA editing in neutrophils in response to tumor induction.

Abstract

Tumor-associated neutrophils (TANs) play dual roles in cancer progression, yet the molecular basis of their reprogramming by tumor cells remains poorly understood. Here, we performed a time-resolved transcriptomic and RNA editome analysis of neutrophils co-cultured with three hepatocellular carcinoma (HCC) cell lines using 293T cells as control. We observed consistent transcriptional remodeling across treatments, with progressive upregulation of pro-tumor genes and downregulation of anti-tumor genes, which were associated with functions of neutrophil chemotaxis, NETosis, metabolic reprogramming, and N1-to-N2 polarization. Concurrently, global A-to-I RNA editing, ADAR expression, together with ADAR1-MDA5-immunity and ADAR2-recoding axes were markedly reduced in HCC-induced neutrophils, compatible with the tumor-driven reprogramming hypothesis. Differential editing analysis revealed three key downregulated recoding sites with distinct evolutionary histories, MED21 (p.Gln145Arg), HSPA1L (p.Asn153Asp), and ZNF397 (p.Tyr481Cys), which may alter transcriptional and stress-regulatory functions of downstream targets. Together, these results indicate a possible link between transcriptional remodeling, RNA editing, and functional polarization of HCC-induced neutrophils. Since our analyses are in silico, the proposed mechanistic links should be interpreted as hypotheses for future validation. Our findings provide an exploratory framework for investigating ADAR-regulated RNA editing in tumor-immune communication.