A recent study published in Nature Cancer shows that intervening in the metabolism of acetic acid by cancer cells through ACSS2 is not only an effective approach, but also an unexpected gain!
The research team of the Wistar Institute in the United States found that inhibiting ACSS2 in cancer cells can transform cancer cells from consumers of acetic acid to producers, and tumor-infiltrating lymphocytes (TILs), mainly composed of T cells, will accept this acetic acid, significantly enhancing their own effector function and proliferative activity, thereby effectively enhancing the anti-tumor immune response. Therefore, ACSS2 is also a promising new anticancer target.
In previous basic research, the Wistar research team has preliminarily elucidated the anti-tumor effect of small molecule ACSS2 inhibitors. This study first analyzed the impact of the immune system on ACSS2 inhibition. Preliminary experiments showed that directly knocking out ACSS2 expression can also effectively suppress cancer, but this anti-tumor effect depends on T cells and NK cells. After clearing these two types of immune cells, the anti-tumor effect of knocking out ACSS2 will also disappear.
RNA sequencing analysis showed that after treatment with small molecule ACSS2 inhibitors, the most significantly upregulated genes in mice were mostly related to antigen presentation, immune cell activation, migration, and infiltration, but had limited impact on gene expression in cancer cells. This indicates that the effectiveness of small molecule ACSS2 inhibitors does depend on immune cells, and in addition to T cells and NK cells, B cells, macrophages, and dendritic cells also participate.
RNA sequencing suggests that ACSS2 inhibitor treatment can effectively activate tumor-infiltrating T cells.
Why are all kinds of immune cells so active? This is because the treatment with ACSS2 inhibitors prevents cancer cells from metabolizing acetic acid through ACSS2, transitioning from a consumer of acetic acid to a producer, while immune cells can efficiently consume this excess acetic acid as an alternative energy source through ACSS1, a member of the same family as ACSS2. CD8+T cells have the highest efficiency in “eating vinegar” and this process is not affected by ACSS2 inhibitors.
The research team also analyzed the immune cells of breast cancer patients, and found that the expression level of ACSS1 in CD8+T cells and other lymphocytes was significantly higher than that of monocytes and cancer cells, and tried to directly supplement acetic acid to increase their efficiency. In the glucose-deficient environment, CD8+T cells can indeed use acetic acid efficiently.
Therefore, in summary, inhibiting ACSS2 can enhance the anti-tumor immune response through two mechanisms: firstly, reducing the metabolism of acetic acid and energy supply by cancer cells through ACSS2, and secondly, allowing excess acetic acid to supply immune cells such as T cells, enhancing the combat power of immune cells.
Although the research team did not evaluate whether ACSS2 inhibitors can synergize with PD-1/L1 inhibitors (only evaluating their efficacy in chemotherapy), immune cells are fully equipped with the help of Tianjiangacetic acid, how can the effectiveness of immunotherapy still be weak?
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Reference
Schug Z T, Peck B, Jones D T, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress[J]. Cancer Cell, 2015, 27(1): 57-71.
Miller K D, O’connor S, Pniewski K A, et al. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer[J]. Nature Cancer, 2023.
Miller K D, Pniewski K, Perry C E, et al. Targeting ACSS2 with a transition-state mimetic inhibits triple-negative breast cancer growth[J]. Cancer Research, 2021, 81(5): 1252-1264.