Cancer Stem Cells Shift Metabolite Acetyl‐Coenzyme A to Abrogate the Differentiation of CD103 ⁺ T Cells

Abstract CD103 ⁺ T cells mediate potent anti‐tumor immune responses and correlate with favorable clinical outcomes in cancer patients. However, the mechanisms by which cancer cells influence the differentiation of these cells remain elusive. Herein, we demonstrate that cancer stem cells (CSCs) play a pivotal role in suppressing CD103 ⁺ T cell differentiation in patients with non‐small cell lung cancer (NSCLC). Specifically, CSCs facilitate the transfer of the metabolite acetyl‐coenzyme A (acetyl‐CoA) into interacting T cells via an exosome‐dependent pathway. This process enhances the acetylation of B lymphocyte‐induced maturation protein 1 (Blimp‐1), a critical transcription factor governing CD103 ⁺ T cell differentiation. Acetylation of Blimp‐1 strengthens its interaction with the E3 ubiquitin ligase LIS1, thereby promoting Blimp‐1 degradation, which ultimately blocks CD103 ⁺ T cell differentiation. Accordingly, targeting CSCs and acetyl‐CoA biosynthesis using CD133 antibody‐conjugated nanoparticles increases tumor‐infiltrating CD8 ⁺ CD103 ⁺ T cells and suppresses tumor growth. Importantly, studies using NSCLC patient‐derived organoids (PDOs) and humanized PDO‐NSG chimeras confirmed that blocking acetyl‐CoA production, exosome secretion from CSCs, and key enzymes involved in Blimp‐1 acetylation and ubiquitination effectively restores CD103 ⁺ T cell differentiation. Altogether, CSC acetyl‐CoA is a key contributor in impairing CD103 ⁺ T cells through programming post‐translational modifications, serving as a promising therapeutic target in anti‐tumor therapy.