Unraveling RELA as a potential dioctyl terephthalate-related target regulates M2-like macrophages to induce an immunosuppressive microenvironment in colorectal cancer: a multi-omics data study by experimental validation

Dioctyl terephthalate (DOTP) has been associated with chronic intestinal inflammation. However, its implications for patients with colorectal cancer (CRC) remain unexplored. This study aimed to identify potential molecular targets and mechanisms involved in DOTP-related remodeling of the CRC microenvironment. Using multiple databases and weighted gene coexpression network analysis, we identified 12 potential DOTP-related CRC targets. Molecular docking (MD) and molecular dynamics simulations (MDS) were conducted to assess the interactions between these targets and DOTP. Notably, potential bindings were observed between DOTP and nine targets. Through the screening of 82 machine learning model combinations, four common targets were identified among the nine candidates, particularly RELA and AR. Importantly, exposure of SW620 and LS513 to DOTP resulted in increased RELA expression and enhanced proliferative and migratory capacities. Furthermore, elevated RELA expression was associated with an immunosuppressive microenvironment and a reduced response to immunotherapy. Single-cell RNA sequencing (scRNA-seq) revealed predominant RELA expression in macrophages, particularly in M2-like Mph_SPP1 cells, which exhibited marked immunosuppressive activity with highly expressed LGALS9. Notably, THP1 cells treated by DOTP resulted in increased mRNA expression levels of RELA and M2 phenotype markers. These findings suggest that dysregulation of the immune microenvironment may represent a critical mechanism underlying the progression of DOTP-related CRC and highlight RELA as a promising therapeutic target for CRC patients with high-risk exposure to DOTP.