Venetoclax Enhances gamma-deltaT cell Antileukemia Activity via Fatty Acid Oxidation in Relapsed Acute Myeloid Leukemia.

Relapse remains a leading cause of death in acute myeloid leukemia (AML), in part because host immune surveillance declines over time. Gamma delta (gamma-delta) T cells contribute to immune surveillance and have been linked to better outcomes in AML. Here we show that gamma-deltaT cells from patients with relapsed AML display reduced effector programs compared with those from patients in complete remission. In a targeted screen of approved AML drugs, the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax emerged as a potent enhancer of gamma-deltaT-cell cytotoxicity against primary AML blasts from both newly diagnosed and relapsed patients. Short ex vivo venetoclax exposure activated gamma-deltaT cells, increased proliferation, and lowered markers of exhaustion, thereby sustaining antileukemia activity over time. Venetoclax also increased mitochondrial respiration (oxidative phosphorylation) and respiratory reserve and shifted metabolism toward fatty acid oxidation. In AML xenograft models, adoptive transfer of venetoclax-pretreated gamma-deltaT cells, including chimeric antigen receptor (CAR)–engineered gamma-deltaT cells, produced superior tumor clearance compared with untreated cells. These findings indicate that venetoclax rejuvenates gamma-deltaT-cell function through metabolic remodeling and supports combining venetoclax with gamma-deltaT-cell–based immunotherapy for relapsed AML. Overall design: This study investigated the effects of venetoclax on the transcriptomic profile of gamma-delta T cells in the context of acute myeloid leukemia (AML). Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors. gamma-delta T cells were isolated and expanded ex vivo under standard conditions. For experimental samples, expanded gamma-delta T cells were treated with venetoclax for 18 hours; untreated gamma-delta T cells from the same donors served as controls. RNA was extracted from gamma-delta T cells (both untreated and venetoclax-treated) using, followed by poly(A) selection and library preparation. Sequencing was performed on an Illumina NovaSeq 6000 platform to generate 150-bp paired-end reads. The dataset includes N = 3 donors with matched gamma-delta T (control) and venetoclax-treated gamma-delta T (experimental) samples. The primary comparison is venetoclax-treated vs untreated gamma-delta T cells.