Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination. Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.