TY - JOUR
T1 - Bezafibrate-driven mitochondrial targeting enhances antitumor immunity and prevents lung cancer via CD8+ T cell infiltration and MDSC reduction
AU - Pan, Jing
AU - Li, Jiaheng
AU - Zhang, Qi
AU - Huang, Mofei
AU - Wang, Yian
AU - You, Ming
N1 - Publisher Copyright:
Copyright © 2025 Pan, Li, Zhang, Huang, Wang and You.
PY - 2025
Y1 - 2025
N2 - Bezafibrate (BEZ) is a drug used to treat hypertriglyceridemia and its long-term use has been associated with reduced risk of cancer in patients with coronary artery disease. Recent studies uncovered that BEZ is a potent modulator of mitochondrial biogenesis through activation of PGC-1α/PPAR complexes, resulting in modulation of lipid metabolism and fatty acid oxidation. Mitochondria impact virtually all processes linked to oncogenesis, and disruption of normal mitochondrial bioenergetics and oxidative phosphorylation (OXPHOS) occurs early during oncogenesis to change the energy metabolism of cancer cells as well as various cells in the tumor microenvironment (TME). Therefore, we synthesized a BEZ analog (Mito-BEZ) that preferentially localizes to mitochondria, thereby enabling lower doses of Mito-BEZ than BEZ to achieve greater efficacy. Our studies demonstrate that Mito-BEZ is significantly more potent than BEZ at inhibiting LUAD cell growth in vitro and inhibiting lung tumorigenesis in preclinical mouse models. Mito-BEZ was also >200-fold more potent than BEZ at inhibiting both complex I and III in LUAD cells. Furthermore, Mito-BEZ suppresses oxidative metabolism in cancer cells while markedly upregulating mitochondrial function in effector CD8+ T cells, resulting in activation of a potent T cell immune response in the TME. Our results show that Mito-BEZ, with its favorable toxicity profile, exhibited a striking inhibitory effect on lung cancer progression and metastasis by targeting a fundamental difference in metabolic plasticity between cancer cells and effector T cells in the TME.
AB - Bezafibrate (BEZ) is a drug used to treat hypertriglyceridemia and its long-term use has been associated with reduced risk of cancer in patients with coronary artery disease. Recent studies uncovered that BEZ is a potent modulator of mitochondrial biogenesis through activation of PGC-1α/PPAR complexes, resulting in modulation of lipid metabolism and fatty acid oxidation. Mitochondria impact virtually all processes linked to oncogenesis, and disruption of normal mitochondrial bioenergetics and oxidative phosphorylation (OXPHOS) occurs early during oncogenesis to change the energy metabolism of cancer cells as well as various cells in the tumor microenvironment (TME). Therefore, we synthesized a BEZ analog (Mito-BEZ) that preferentially localizes to mitochondria, thereby enabling lower doses of Mito-BEZ than BEZ to achieve greater efficacy. Our studies demonstrate that Mito-BEZ is significantly more potent than BEZ at inhibiting LUAD cell growth in vitro and inhibiting lung tumorigenesis in preclinical mouse models. Mito-BEZ was also >200-fold more potent than BEZ at inhibiting both complex I and III in LUAD cells. Furthermore, Mito-BEZ suppresses oxidative metabolism in cancer cells while markedly upregulating mitochondrial function in effector CD8+ T cells, resulting in activation of a potent T cell immune response in the TME. Our results show that Mito-BEZ, with its favorable toxicity profile, exhibited a striking inhibitory effect on lung cancer progression and metastasis by targeting a fundamental difference in metabolic plasticity between cancer cells and effector T cells in the TME.
KW - Bezafibrate
KW - CD8
KW - complex III
KW - mitochondria-targeted compound
KW - tumor immune microenvironment
UR - http://www.scopus.com/inward/record.url?scp=105003749577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=105003749577&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2025.1539808
DO - 10.3389/fimmu.2025.1539808
M3 - Article
C2 - 40303399
AN - SCOPUS:105003749577
SN - 1664-3224
VL - 16
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1539808
ER -