Amino Acid Metabolic Reprogramming Drives Doramectin-Enhanced CD8+ T Cell Immunity and Tumor Control

Authors

• Sedigheh Taghinezhad-S, Henry Ford HealthFollow
• Amirhossein Mohseni, Henry Ford HealthFollow
• Vincenzo Casolaro
• Zhongwei Lv
• Dan Li

Recommended Citation

Taghinezhad-S S, Mohseni A, Casolaro V, Lv Z, Li D. Amino Acid Metabolic Reprogramming Drives Doramectin-Enhanced CD8+ T Cell Immunity and Tumor Control. Cancer Res 2026; 86(7):1.

Document Type

Conference Proceeding

Publication Date

4-26-2026

Publication Title

Cancer Res

Keywords

Oncology

Abstract

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.

Volume

86

Issue

7

First Page

1