Recent studies have reported direct antitumor effects of mannose, a natural six-carbon monosaccharide, in the treatment of cancer. Herein, we utilized cancer cell lines, animal models, organoids and experimental techniques such as multi-omics and cellular experiments to investigate the regulatory effects of mannose on NSCLC growth and the inflammatory microenvironment. We demonstrated that mannose can inhibit cancer cell growth, inflammatory cell infiltration and inflammatory cytokine expression in NSCLC tissue, and enhance the antitumor efficacy of immune checkpoint inhibitor both