Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer

Chenglong Li; Tingfang Gao; Qiuling Zhao; Zhi Li; Zhidong Wang; Shuaishuai Ding; Mengsi Zhang; Yan Qin; Xinwen Xue; Xiao Zhang; Gan Tian; Xiu-Wu Bian; Yi Yang

doi:10.1016/j.canlet.2025.217991

Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer

Cancer Lett. 2025 Aug 16:633:217991. doi: 10.1016/j.canlet.2025.217991. Online ahead of print.

Authors

Chenglong Li¹, Tingfang Gao², Qiuling Zhao¹, Zhi Li¹, Zhidong Wang², Shuaishuai Ding¹, Mengsi Zhang¹, Yan Qin¹, Xinwen Xue¹, Xiao Zhang¹, Gan Tian³, Xiu-Wu Bian⁴, Yi Yang⁵

Affiliations

¹ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
² Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, China.
³ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, China. Electronic address: tiangan09@163.com.
⁴ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China. Electronic address: bianxiuwu@263.net.
⁵ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, China. Electronic address: yiyang-09@tmmu.edu.cn.

PMID: 40825468
DOI: 10.1016/j.canlet.2025.217991

Abstract

Triple-negative breast cancer (TNBC) remains a challenging malignancy to treat, underscoring the urgent need to explore novel and effective therapeutic targets. In this study, we found that carnitine palmitoyltransferase 1A (CPT1A), the central and rate-limiting enzyme for fatty acid oxidation (FAO) in lipid metabolism, is significantly correlates with poor survival outcomes in TNBC patients and is highly expressed in TNBC patient samples. Inhibition of CPT1A greatly suppresses TNBC tumor growth. Mechanistically, we discovered that beyond disruption of the canonical metabolic functions for tumor cell survival, CPT1A depletion markedly triggers cGAS/STING activation due to lipid accumulation-induced elevation of mitochondrial reactive oxygen species (ROS), leading to mitochondrial damage and subsequent mtDNA cytosolic release, which ultimately promotes neutrophil intratumoral infiltration and acquisition of a tumor-killing phenotype, thereby effectively inhibiting tumor growth. Our current findings suggest that inhibition of CPT1A potently activates the cGAS/STING pathway, significantly enhancing the engagement of neutrophils for tumor abrogation.

Keywords: CPT1A; Fatty acid oxidation; Neutrophils; Triple-negative breast cancer (TNBC); cGAS/STING.