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Targeting CPT1A triggers cGAS/STING activation to engage neutrophils for tumor elimination

ABSTRACT: Lipid metabolism plays an important role in tumor progression and immune evasion. Targeting fatty acid oxidation (FAO) has been shown to be a promising approach to treat cancers. However, the impact of FAO inhibition on tumor immune microenvironment is still less understood. In this study, we found that inhibiting FAO by targeting CPT1A dramatically triggers cGAS/STING activation through inducing cytoplasmic leakage of mitochondrial DNA. This leads to the infiltration of neutrophils into tumors and drive anti-tumor effects of a subset of neutrophils, which plays a crucial role in inhibiting tumor growth. Our current findings suggest that CPT1A could be a promising target for TNBC therapy and, moreover, we uncover an essential anti-tumor role of neutrophils upon cGAS/STING activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE289953 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Carnitine palmitoyl transferase 1 (CPT1) is a rate-limiting enzyme for long chain fatty acid oxidation (FAO) in cardiac mitochondria. In adult hearts, CPT1b predominates, while CPT1a is co-expressed at lower levels. Pathological stress on the heart is known to induce CPT1a expression, but it’s role in pathological remodeling is unknown. CPT1 isoform expression was assayed in myocardium of human heart failure (HF) patients with nonischemic cardiomyopathy (NICM). To explore the role of CPT1a upregulation in response to pathological stress, mice were subjected to cardiac pressure overload via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, AAV9 mediated overexpression of CPT1a (AAV9.cTNTN.Cpt1a). MiR370, known to suppress hepatic CPT1a, was also overexpressed to determine if miR370 regulates cardiac CPT1a expression. CPT1a protein was elevated and miR370 reduced in myocardium of male and female NICM patients (204% vs. non-failing unused donor hearts), as well as in failing mouse hearts. AAV mediated miR370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac specific CPT1a knockout mice (csCPT1a ko) exacerbated adverse remodeling during TAC, causing severe dysfunction and increased mortality. In contrast, CPT1a overexpression (2.8 fold), attenuated impaired ejection fraction (EF, by 54%), fractional shortening (FS, 65%) and +/-dp/dt, and reduced ANP expression and heart mass/tibia length vs. PBS-infused TAC hearts (p<0.05). Delivery of AAV9.cTnT.Cpt1a 4 wks after TAC surgery during cardiac dysfunction, led to significant rescue of EF and FS vs. animals receiving empty virus and mitigated the exacerbated dysfunction of csCPT1a ko hearts at 4 wks TAC. RNA-seq and reverse transcription-quantitative PCR revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic and cell death gene programs in both sham and TAC hearts, irrespective of changes in FAO. The effects of CPT1a in the heart extend beyond FAO and include a non-canonical regulation of cardiac gene programs. In addition to an animal model of HF, CPT1a upregulation occurs in failing human hearts, and is a critical and cardioprotective adaptation to pathological stress that attenuates adverse cardiac remodeling.

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Targeting CPT1A triggers cGAS/STING activation to engage neutrophils for tumor elimination

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