<p>Colorectal cancer (CRC) remains a formidable therapeutic challenge, with persistent difficulties in developing therapies that simultaneously target tumor cell proliferation and the tumor immune microenvironment (TIME). 8-Gingerol (8-G), a bioactive natural compound, has shown anti-tumor potential; however, its mechanisms in the evolution of CRC and TIME are yet unknown. Through comprehensive investigation using multiple CRC cell lines and in vivo models, experiments conducted both in vitro and in vivo verified that 8-G markedly inhibited CRC cell tumorigenesis. Mechanistically, 8-G exerted dual anti-tumor effects: it directly induced a coordinated cell death program known as PANoptosis in CRC cells, characterized by concurrent activation of apoptotic, pyroptotic, and necroptotic pathways, and simultaneously reprogrammed tumor-associated macrophages (TAMs) toward the anti-tumor M1-type by downregulating LIF. We further established LIF as a key immunosuppressive mediator in CRC, where its expression correlates with poor patient prognosis and promotes M2-TAMs polarization. Further analyses showed 8-G blocked LIF-triggered pyroptosis during CRC cell-TAMs crosstalk, while promoting interferon-γ (IFN-γ) expression and secretion in TAMs via LIF suppression—key changes that remodel the TIME toward anti-tumor immunity. Our findings unveil the dual action of 8-G that not only inhibits CRC cells directly but also remodels the immunosuppressive TIME by targeting LIF, thereby promoting anti-tumor immunity. This study highlights the therapeutic potential of 8-G and identifies LIF as a promising target for CRC immunotherapy.</p> Graphical abstract <p></p>