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

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Abstract
Background 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. Methods 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). Evaluate the functional states of T cells in different BCAA strata using single - cell gene scores. In vivo and in vitro experiments were conducted to verify the regulation of BCAA treatment on the growth of prostate cancer xenografts and cancer cells. In addition, the Cancer Genome Atlas (TCGA) database was used to determine the clinical feature correlation of the key gene ACAT1 and to study its crosstalk in BCAA metabolism and prostate cancer immune regulation. Results 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. Conclusions 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. This study provides new therapeutic targets and theoretical support for prostate cancer treatment by targeting BCAA-ACAT1-CS acetylation axis.