Carboxyamidotriazole orotate regulates cancer-associated fibroblasts function and remodels the tumor microenvironment in pancreatic cancer

doi:10.16352/j.issn.1001-6325.2026.08.1068

Abstract

Abstract: Objective Cancer-associated fibroblasts(CAFs) represent the predominant stromal cell population in the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) and play critical roles in tumor progression and the development of therapeutic resistance. CAFs not only participate in stromal remodeling through abnormal proliferation and migration but also regulate the tumor microenvironment by secreting various metabolites that support tumor cell growth. Carboxyamidotriazole orotate(CTO) is a Complex Ⅰ inhibitor with antitumor activity; however, its effects on the biological functions and metabolic secretory profile of CAFs within the tumor microenvironment remain unclear. The present study aims to investigate the regulatory effects of CTO on CAF biological functions and metabolic secretion in pancreatic cancer and to explore its potential role in remodeling the tumor microenvironment. Methods SRB assays and Western blot analysis were performed to evaluate the effects of CTO on CAF proliferation and activation status. Transcriptome sequencing was used to analyze the alterations in CAF-related biological pathways following CTO treatment. In addition, metabolomic analysis of cell culture supernatants was conducted to characterize changes in the secreted metabolite profile of CAFs, thereby assessing the impact of CTO on metabolic support within the tumor microenvironment. Results CTO treatment significantly inhibited CAF proliferation and activation. Transcriptomic analysis revealed that CTO regulated multiple signaling pathways associated with stromal remodeling and tumor-promoting functions in CAFs, thereby attenuating their pro-tumor activity. Metabolomic analysis further demonstrated that CTO altered the composition of metabolites secreted by CAFs and affected the supply of key metabolites in the tumor microenvironment, consequently reducing the metabolic support provided by CAFs for tumor cell survival and growth. Conclusions CTO can remodel the pancreatic cancer tumor microenvironment by inhibiting CAF proliferation and regulating their metabolic secretory profile, thereby influencing tumor progression. These findings provide new experimental evidence supporting strategies that target stromal cells to modulate the tumor microenvironment.

Key words: pancreatic ductal adenocarcinoma, carboxyamidotriazole orotate, cancer-associated fibroblasts, metabolic reprogramming, tumor microenvironment

CLC Number:

R735.9

QIN Ziyi, XU Yeting, ZOU Jiaming, MA Jinyang, WANG Yucheng, JU Rui, GUO Lei. Carboxyamidotriazole orotate regulates cancer-associated fibroblasts function and remodels the tumor microenvironment in pancreatic cancer[J]. Basic & Clinical Medicine, 2026, 46(8): 1068-1075.

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