Language
English
Publication Date
5-5-2026
Journal
bioRxiv
DOI
10.64898/2026.05.01.722261
PMID
42146389
PMCID
PMC13174484
PubMedCentral® Posted Date
5-5-2026
PubMedCentral® Full Text Version
Pre-Print
Abstract
The metastatic progression of breast cancer involves complex interactions between tumor cells and immune cells, including T cells that exert cytotoxic pressure to limit metastasis. Tumor cells reprogram their metabolism to evade immune surveillance, a critical step to achieving metastatic outgrowth. Using an unbiased CRISPR screen targeting metabolism-related genes and a clinically relevant spontaneous metastasis mouse model, we identified CPT1A, the rate-limiting enzyme in fatty acid β-oxidation, as a suppressor of immune-dependent metastasis. Loss of CPT1A enhances lung metastasis in immunocompetent mice, but not Rag1 KO mice that lack mature lymphocytes. Loss of CPT1A triggers cytosolic mitochondrial DNA (mtDNA) release via the mPTP pore. Cytosolic mtDNA release triggers a STING-dependent inflammatory response, creating an environment that impairs CD8+ T cell function, promoting metastatic outgrowth. Among breast cancer patients, low CPT1A expression correlates with poor survival when CD8+ T cell infiltration is high. These findings reveal an extrinsic role for CPT1A in immune-tumor dynamics and suggest therapeutic opportunities targeting inflammation in metastatic breast cancer.
Published Open-Access
yes
Recommended Citation
Wang, Xiaoyong; Chou, Shu-Ting; Hwang, Yoonha; et al., "CPT1A Loss Promotes Lung Metastasis in Immune-Competent Mice via a Mechanism of mtDNA Release and Chronic Activation of Sting Pathway" (2026). Faculty, Staff and Students Publications. 8027.
https://digitalcommons.library.tmc.edu/baylor_docs/8027