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FEN1 inhibitor SC13 promotes CAR-T cells infiltration into solid tumours through cGAS-STING signalling pathway. | LitMetric

AI Article Synopsis

  • CAR-T-cell immunotherapy shows great promise for blood cancers but struggles with solid tumors due to inefficient T-cell infiltration.
  • Flap structure-specific endonuclease 1 (FEN1) plays a crucial role in DNA repair and is often overexpressed in cancer; inhibiting it may enhance cancer treatment.
  • Combining FEN1 inhibitors like SC13 with CAR-T-cell therapy increases double-stranded DNA in tumor cells, which boosts chemokine secretion and helps CAR-T cells effectively infiltrate solid tumors, improving anti-tumor immunity.

Article Abstract

It is well known that chimeric antigen receptor T-cell immunotherapy (CAR-T-cell immunotherapy) has excellent therapeutic effect in haematological tumours, but it still faces great challenges in solid tumours, including inefficient T-cell tumour infiltration and poor functional persistence. Flap structure-specific endonuclease 1 (FEN1), highly expressed in a variety of cancer cells, plays an important role in both DNA replication and repair. Previous studies have reported that FEN1 inhibition is an effective strategy for cancer treatment. Therefore, we hypothesized whether FEN1 inhibitors combined with CAR-T-cell immunotherapy would have a stronger killing effect on solid tumours. The results showed that low dose of FEN1 inhibitors SC13 could induce an increase of double-stranded broken DNA (dsDNA) in the cytoplasm. Cytosolic dsDNA can activate the cyclic GMP-AMP synthase-stimulator of interferon gene signalling pathway and increase the secretion of chemokines. In vivo, under the action of FEN1 inhibitor SC13, more chemokines were produced at solid tumour sites, which promoted the infiltration of CAR-T cells and improved anti-tumour immunity. These findings suggest that FEN1 inhibitors could enable CAR-T cells to overcome poor T-cell infiltration and improve the treatment of solid tumours.

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Source
http://dx.doi.org/10.1111/imm.13681DOI Listing

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