Mycobacterium tuberculosis (Mtb) produces D-serine under hypoxic conditions to suppress CD8⁺ T cell-mediated immunity in mice. The study reveals that Mtb induces the expression of Rv0884c, a phosphoserine aminotransferase, to produce D-serine under hypoxia. This D-serine inhibits IFN-γ production by CD8⁺ T cells, thereby reducing the ability of macrophages to restrict Mtb. Mechanistically, D-serine interacts with WDR24 and inhibits mTORC1 activation in CD8⁺ T cells, leading to decreased T-bet expression and reduced IFN-γ production. These findings suggest that Mtb uses hypoxia adaptation to suppress adaptive anti-TB immunity by enhancing D-serine biosynthesis, which in turn inhibits CD8⁺ T cell responses. The study highlights the role of D-serine in Mtb immune evasion and provides insights into the metabolic strategies of Mtb to survive in the hypoxic environment of macrophages. The research also identifies the molecular pathway through which D-serine inhibits mTORC1 and T-bet, contributing to the suppression of CD8⁺ T cell function. Overall, the study underscores the importance of understanding Mtb's metabolic adaptations in the context of host immune responses.Mycobacterium tuberculosis (Mtb) produces D-serine under hypoxic conditions to suppress CD8⁺ T cell-mediated immunity in mice. The study reveals that Mtb induces the expression of Rv0884c, a phosphoserine aminotransferase, to produce D-serine under hypoxia. This D-serine inhibits IFN-γ production by CD8⁺ T cells, thereby reducing the ability of macrophages to restrict Mtb. Mechanistically, D-serine interacts with WDR24 and inhibits mTORC1 activation in CD8⁺ T cells, leading to decreased T-bet expression and reduced IFN-γ production. These findings suggest that Mtb uses hypoxia adaptation to suppress adaptive anti-TB immunity by enhancing D-serine biosynthesis, which in turn inhibits CD8⁺ T cell responses. The study highlights the role of D-serine in Mtb immune evasion and provides insights into the metabolic strategies of Mtb to survive in the hypoxic environment of macrophages. The research also identifies the molecular pathway through which D-serine inhibits mTORC1 and T-bet, contributing to the suppression of CD8⁺ T cell function. Overall, the study underscores the importance of understanding Mtb's metabolic adaptations in the context of host immune responses.