CPT1A inhibition alleviates plasmacytoid dendritic cell-mediated immune suppression in colon cancer through fatty acid oxidation modulation

Background: The tolerization of plasmacytoid dendritic cells (pDCs) within the tumor microenvironment facilitates immune evasion, thereby significantly limiting the efficacy of Cancer Immunotherapy. Metabolic regulators are crucial in determining immune cell fate. However, the specific metabolic modifications influencing tumor-associated pDCs (TA-pDCs) are largely uncharacterized.

Methods: We isolated TA-pDCs from patients with colon Cancer and mouse models for RNA Sequencing detection and immunofluorescence staining. Further, in vitro and in vivo models of colon Cancer were used to explore the underlying mechanisms of the fatty acid oxidation (FAO) regulatory pathway of TA-pDCs and its immunosuppressive function.

Results: Peroxisome Proliferator-activated Receptor gamma pathway promotes FAO in TA-pDCs by upregulating the expression of carnitine palmitoyltransferase-1A (CPT1A). The inhibition of CPT1A significantly reduced the immunosuppressive checkpoint inducible co-stimulator ligand (ICOSL) and increased the levels of the immune-activating protein OX40L and pro-inflammatory cytokines interferon-α and tumor necrosis factor-α. These alterations enhanced CD8⁺ T-cell functionality and diminished the generation of regulatory T cells, thereby bolstering antitumor immunity. The efficacy of combined immunotherapy using anti-ICOSL and anti-programmed cell death 1-ligand 1 antibodies was markedly improved in murine models of colon Cancer.

Conclusions: These findings elucidate the molecular mechanism of CPT1A-mediated FAO in TA-pDCs and its implications in immune evasion, suggesting a novel therapeutic strategy for colon Cancer Immunotherapy.

Colon Cancer; Dendritic; Immunosuppression; Immunotherapy; Tolerance.