Acute myeloid leukemia is an aggressive hematological disease, where cancer cells down-regulate antigen presentation and immune-stimulatory molecules. Here, we show that genetic deletion of protein neddylation rewires the human AML proteome towards an immunogenic phenotype, while suppressing cholesterol biosynthesis. As a result, neddylation-deficient AML cells respond more potently to TLR agonists in vitro. Using genome-wide CRISPR/Cas9 screens, we have identified mTOR as an important pathway in deficient cells. Inhibition of lipid metabolism by simvastatin in primary human monocytes amplifies response to LPS, which is governed by mTOR and JAK/STAT pathways. In mice, simvastatin fine-tunes the inflammatory response driven by LPS and polarizes myeloid cells to a stimulatory phenotype. While neither simvastatin nor LPS show efficacy against murine C1498 tumors, a combination of the agents delays tumor growth in mice. Altogether, our results uncover a previously unknown function of protein neddylation in governing the response to TLR stimulation and propose the therapeutic potential of statin drugs in immunotherapy against hematological malignancies.