Fusobacterium nucleatum Enhances Immune Escape in Colorectal Cancer by Inducing H3K18 Lactylation of CD274 (PD-L1)...

Fusobacterium nucleatum (Fn), an intratumoral pathogenic bacterium, is confirmed to be associated with tumor progression in colorectal cancer (CRC). To evaluate CD8⁺ T cell function against CRC cells, their cytotoxicity was determined via live/dead staining and ELISA, while proliferation was assessed using the CFSE assay. CD274 (PD-L1) expression in CRC was quantified by qPCR, flow cytometry, and immunofluorescence. Lactate accumulation in CRC cells was measured using LDHA and lactate assay kits. Histone lactylation levels were analyzed by Western blot. Chromatin immunoprecipitation was applied to examine the abundance of H3K18 lactylation (H3K18la) at the CD274 promoter region. Finally, Annexin V/PI staining was employed to analyze the apoptosis rate of CRC cells. Fn treatment inhibited the anti-tumor immune capacity of CD8⁺ T cells against CRC cells and increased PD-L1 expression. Fn stimulation promoted lactate accumulation in CRC cells and enhanced H3K18la levels. Mechanistic studies revealed enrichment of H3K18la. Fn treatment induced H3K18la of PD-L1, upregulating its expression, suppressing CD8⁺ T cell immune activity, and promoting immune escape in CRC. This study demonstrates that Fn is crucial in CRC immune escape, proposing that regulating Fn abundance represents a novel strategy to enhance immunotherapy effectiveness.