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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. [Display omitted] • GRP78 entered macrophages promotes lipid catabolism. • Unsaturated fatty acids activate the transcription factor PPARγ of macrophages. • GRP78 mediated the domestication of tumor cells to macrophages. • GRP78 maintains the immunosuppressive microenvironment of the tumor. [ABSTRACT FROM AUTHOR]

[Display omitted] • BPIS specifically inhibited breast cancer via blocking the conversion of SFA to MUFA. • VT and SA were the anti-breast cancer active ingredients of BPIS. • GRP78 was the target of VT and SA and mediated the conversion of SFA to MUFA. Breast cancer is the most frequently diagnosed malignant tumor in women. Foxtail millet is an important cereal food and exhibits a wide range of nutrition. We previously extracted total polyphenols composed of 12 compounds from foxtail millet bran (named BPIS). In this study, we find that BPIS inhibits the proliferation of breast cancer cells by restraining the cellular membrane synthesis via suppressing the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA). Mechanically, BPIS decreases the glucose regulated protein 78 (GRP78) level, which further inhibits the expression of SREBP-1 and downstream-target SCD1. Combining molecular docking, MTT screening and in vivo model, we ultimately identify that vitexin and syringic acid are the main active ingredients. Our data showed that the combination of vitexin and syringic acid suppress the proliferation of breast cancer cells, which support further study of BPIS as a new dietary assistant strategy to improve breast cancer. [ABSTRACT FROM AUTHOR]