Amino acid metabolic reprogramming drives doramectin-enhanced CD8⁺ T cell immunity and tumor control

CD8⁺ T-cell metabolic programming is a pivotal determinant of antitumor immunity, yet strategies to therapeutically activate these pathways remain limited. Here, we show that doramectin, a clinically available macrocyclic lactone, enhances antitumor immunity by reprogramming amino acid metabolism in CD8⁺ T-cells. In tumor-bearing mice, doramectin promoted amino acid-dependent metabolic engagement, strengthened effector function, supported memory differentiation, and increased CD8⁺ T-cell infiltration into the tumor microenvironment, collectively resulting in durable tumor control. These findings suggest that doramectin induces a metabolically reinforced T-cell state capable of sustaining immunosurveillance. Mechanistically, doramectin enhanced amino acid-linked bioenergetic and biosynthetic pathways, consistent with elevated metabolic fitness and immune competence. A critical requirement for this metabolic reprogramming was revealed through the role of the gut microbiota. Doramectin treatment led to a selective microbial shift, with specific taxa trafficking to lymphoid tissues where they delivered signals required for CD8⁺ T-cell metabolic engagement. When these microbial signals were disrupted, the metabolic reprogramming and corresponding antitumor effects failed to manifest, indicating that the microbiota acts as a permissive metabolic cofactor rather than an autonomous initiator of immunity. Together, these results define a metabolism-centered mechanism by which doramectin enhances antitumor immunity through microbiota-enabled amino acid metabolic reprogramming of CD8⁺ T-cells. This work highlights the therapeutic potential of targeting amino acid metabolism, supported by microbial cues, to improve T-cell mediated immunotherapy in solid tumors and underscores the importance of host-microbe metabolic crosstalk in shaping antitumor immune responses.