Histone lactylation inhibits RARy expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARy is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARy interacts with tumor necrosis factor receptor -associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor kB signaling. However, tumor -derived lactate fuels H3K18 lactylation to prohibit RARy gene transcription in macrophages, consequently enhancing interleukin-6 (IL -6) levels in the TME and endowing macrophages with tumor -promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARy to inhibit TRAF6IL-6-STAT3 signaling. This study unravels lactate -driven macrophage function remodeling by inhibition of RARy expression and highlights NDGA as a candidate compound for treating CRC.