ChREBP-mediated choline deprivation and chemokine secretion shape TAMs to promote immune evasion

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy. Aberrant choline metabolism is emerging as a defining hallmark of cancer. However, its impact on antitumor immunity remains largely unclear. Carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation impels tumor-associated macrophages (TAMs) reprogramming and maintains an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacts with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CXCL1, as well as choline transporter SLC44A1. As such, high expression of CCL2 and CXCL1 expression promotes recruitment of TAMs and MDSCs in the TME. Tumor cells with high SLC44A1 expression compete consuming choline with M1-like TAMs, inhibiting cGAS-STING signaling and promoting the polarization of M1 to M2 macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression is associated with poor clinical outcome in CRC. Inhibiting ChREBP reduces M2-like TAMs and MDSCs to enhance anti-tumor immunity, suggesting ChREBP as a potential immunotherapy target in cancer. Overall design: To elucidate the mechanisms underlying ChREBP-mediated antitumor immunity, we subjected shNC and Chrebp-deficient MC38 tumors (in C57BL/6 mice) to RNA sequencing (RNA-Seq). BMDMs were incubated with LPS and IFN-? for 4 h, followed by treatment with fresh RPMI-1640 containing 200 µM choline for 24 h. Comparative gene expression profiling analysis of RNA-seg data for tumor tissues (from shNC/shChrebp MC38-bearing C57BL/6 mice).