Sin1-mTORC2 Augments Lipid Anabolism of Tumor-associated Macrophages to Limit the Type I Interferon-dependent Anti-tumor Immunity

The biological consequences and mechanisms of metabolic reprogramming of macrophages in the tumor microenvironment (TME) remain largely elusive. Here we showed, in part by myeloid-specific ablation of Sin1, a key component of mammalian target of rapamycin complex (mTORC) 2, that the Sin1-mTORC2-Akt-sterol regulatory element-binding proteins (SREBPs) signaling was augmented in tumor-associated macrophages (TAMs), leading to excessive lipid synthesis and accumulation, which consequently impaired the STING-dependent type I interferon production and CD8+ T cell mediated anti-tumor immunity. The ability of Sin1 deficiency in TAMs to inhibit lipid synthesis and enhance anti-tumor immunity could be blunted by the accumulation of cholesterol/lipids in TAMs. Furthermore, genetic ablation of Sin1 in TAMs or pharmacologic inhibition of lipid anabolism acted synergistically with immune checkpoint blockade (ICB)-based cancer therapy to control tumor growth. Finally, elevated Sin1-mTORC2-Akt activity and lipid anabolism as well as decreased type I IFN responses were all observed in TAMs from human colon cancers and tightly associated with poor patient survival. Together, our study uncovers a novel role of Sin1-regulated lipid anabolic pathway in TAMs which acts as a metabolic checkpoint for anti-tumor immunity via limiting a STING-dependent type I IFN response. Overall design: 1. To understand how Sin1 may regulate the anti-tumor activity of TAMs at the molecular level, we isolated WT and Sin1-deficient TAMs from day14 Lewis lung carcinoma (LLC)-bearing Sin1fl/fl (WT) and LysMCre;Sin1fl/fl (cKO) mice to perform RNA-seq. 2. To understand if Sin1 deletion may specifically affect type I IFN signaling in TAMs but not peripheral macrophages, we compared the transcriptional profile in TAMs with that from splenic macrophages in day14 LLC-bearing WT mice.