ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion

Abstract

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. Here, we found that carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS-STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the TME and propose ChREBP as a potential immunotherapeutic target in cancer.