Single-Cell Dissection of BCAA Metabolism Unveils  ACAT1-Dependent CS Acetylation as a Metabolic Checkpoint for Immunosuppression in Prostate Cancer

The catabolism of branched-chain amino acids (BCAA) usually drives the growth of cancer cells, but the role and mechanism of BCAA in the progression of prostate cancer and the formation of the immunosuppressive microenvironment remain unclear.In this study, single-cell sequencing technology was used to analyze the compositional differences in the tumor immune microenvironment of different BCAA catabolism levels (LOW/Med/HIGH). It was found that BCAA-HIGH inhibited the infiltration, cytotoxicity, and proliferation of CD8 T cells, which impaired the anti-tumor immune response of T cells. Mechanistically, this study identified that ACAT1, in response to BCAA, not only promoted the malignant proliferation of prostate cancer cells but also promoted the acetylation modification of citrate synthase, leading to increased citrate synthase activity and citrate production, which promoted the formation of an immunosuppressive microenvironment and further led to the malignant progression of prostate cancer. In summary, the exploration of the BCAA-ACAT1-CS acetylation axis expands our understanding of the role of BCAA in prostate cancer, identifies ACAT1 as a target with dual roles in metabolism and post-translational modification (PTM), and it may become a new target for metabolic/immunotherapy of prostate cancer in the future.