Name:Mus musculus

Cancer immunotherapies have achieved unprecedented success in clinic but remain largely ineffective in some major types of cancer such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumour microenvironment of resistant cancers for developing new intervention strategies. Here we identify a metabolic cue determining unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors to directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumour functions in colorectal cancer. Analysis of a large human CRC cohort reveals an asynchronous pattern of the cholesterol biosynthesis flux leads to abnormal accumulation of distal cholesterol precursors in tumour microenvironment. Inhibiting the immediately upstream enzyme of distal cholesterol precursors by ketoconazole, a clinically approved drug, reduces Th17 population and tumour progression in a preclinical CRC model. Our study therefore reveals a new immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.