TSPAN7 inhibits pancreatic cancer progression by suppressing DNA double-strand break repair and enhances sensitivity to immunochemotherapy

Abstract

Tetraspanin 7 (TSPAN7) plays a crucial role in cancer progression; however, its correlation with pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aimed to analyse TSPAN7 expression and prognostic value in PDAC by integrating data from public databases and our PDAC cohort. We evaluated the effect of TSPAN7 on PDAC cell proliferation and apoptosis using cell-based assays and mouse xenograft models. Furthermore, molecular biology techniques, including RNA sequencing and liquid chromatography-tandem mass spectrometry, were used to explore underlying mechanisms. Notably, TSPAN7 was significantly downregulated in PDAC tissues and was identified as a favourable prognostic biomarker for PDAC patients. Meanwhile, TSPAN7 overexpression inhibited PDAC cell proliferation and promoted apoptosis in vitro. In mice, TSPAN7 decelerated tumour growth and promoted CD8 + T cell infiltration, consequently enhancing the efficacy of immunochemotherapy against PDAC. Mechanistically, TSPAN7 inhibited RAD51-associated protein 1-mediated DNA double-strand break repair, activating the cGAS-STING signalling pathway to induce type I interferon production. Overall, TSPAN7 inhibits PDAC cell growth and enhances the anti-tumour immune response, indicating its potential as a promising therapeutic target for PDAC.

Keywords: DNA double-strand break repair; Immunochemotherapy; Pancreatic ductal adenocarcinoma; RAD51AP1; TSPAN7; cGAS–STING signalling pathway.