Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity
Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA's direct effects on cancer cells are well described, its impact on CD8 T cells [cytotoxic T lymphocytes (CTLs)] remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell-based immunotherapies.
Authors
- Luigi Nezi (ORCID: https://orcid.org/0000-0002-4670-7656)
- Alessia Loffreda (ORCID: https://orcid.org/0000-0003-4523-5666)
- Tiziano Dallavilla (ORCID: https://orcid.org/0000-0002-5653-3741)
- Carlotta Catozzi (ORCID: https://orcid.org/0000-0002-1028-1489)
- JOHN A. JUN. MCLEAN (ORCID: https://orcid.org/0000-0001-8918-6419)
- Katrina L. Leaptrot (ORCID: https://orcid.org/0000-0002-9266-145X)
- Martin H. Schaefer (ORCID: https://orcid.org/0000-0001-7503-6364)
- Carina B. Nava Lauson (ORCID: https://orcid.org/0000-0001-9494-6865)
- Sara Sdelci (ORCID: https://orcid.org/0000-0003-1330-4364)
- Sarah‐Maria Fendt (ORCID: https://orcid.org/0000-0001-6018-9296)
- Tiziana Bonaldi (ORCID: https://orcid.org/0000-0003-3556-1265)
- Stacy D. Sherrod (ORCID: https://orcid.org/0000-0002-2346-230X)
- Simona Rodighiero (ORCID: https://orcid.org/0000-0003-4236-7823)
- Ilir Sheraj (ORCID: https://orcid.org/0000-0001-6020-0256)
- Roberta Noberini (ORCID: https://orcid.org/0000-0002-7267-1079)
- Simona G. Codreanu (ORCID: https://orcid.org/0000-0003-4435-812X)
- Silvia Tiberti (ORCID: https://orcid.org/0000-0003-2141-2365)
- Teresa Manzo (ORCID: https://orcid.org/0000-0001-8552-3625)
- Mattia Ballerini (ORCID: https://orcid.org/0009-0009-1934-9644)
- Mohamed Faisal Kassir (ORCID: https://orcid.org/0000-0003-3501-1802)
- B. Ogretmen
- Juan Fernández-García
- Martina Romeo
- Sara Gennari
- Alexandra C. Schrimpe-Rutledge
Institutions
- Medical University of South Carolina (US)
- Vita-Salute San Raffaele University (IT)
- University of Milan (IT)
- Vanderbilt University (US)
- VIB-KU Leuven Center for Cancer Biology (BE)
- MUSC Hollings Cancer Center (US)
- Virginia Innovation Partnership Corporation (US)
- Centre for Genomic Regulation (ES)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University of Turin (IT)
- European Institute of Oncology (IT)
- Politecnico di Milano (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-03-27
- DOI
- https://doi.org/10.1126/sciimmunol.aeb1459
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00