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<p>Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases. Current treatments often cause systemic side effects or lead to drug resistance, prompting the development of new therapies targeting tumors and related cells simultaneously. Cancer-associated fibroblasts (CAFs) are crucial stromal cells within the tumor microenvironment (TME), making them potential targets for therapy. Previously, we found that the CB1 receptor agonist ACPA has anti-tumor effects on NSCLC, inhibiting pathways such as Akt/PI3K, JNK, glycolysis, the citric acid cycle, and the urea cycle both in vitro and in vivo. We hypothesize that ACPA could enhance therapy by inhibiting the transformation of lung fibroblasts into CAFs via exosomes. Control and ACPA-treated NSCLC cell exosomes exhibited similar size, PDI, ZP, and high expression of CD9, CD63, and CD81. ACPA-treated exosomes showed reduced levels of miR-21 and miR-23. These exosomes decreased fibroblast viability within 12&#xa0;h by disrupting pentose phosphate, lipid, and amino acid metabolism, and by lowering PDPN, α-SMA, and FAP expressions. This research highlights ACPA as a promising chemotherapeutic agent, capable of improving NSCLC treatment and reprogramming the TME with more targeted therapies.</p>

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ACPA prevents lung fibroblast-to-CAF transformation by reprogramming the tumor microenvironment through NSCLC-derived exosomes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月28日

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  • Özge Boyacıoğlu,
  • Berfin Deniz Kalali,
  • Tuba Reçber,
  • Dilek Gelen-Gungor,
  • Emirhan Nemutlu,
  • İpek Eroğlu,
  • Nedret Kılıç,
  • Petek Korkusuz

摘要

Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases. Current treatments often cause systemic side effects or lead to drug resistance, prompting the development of new therapies targeting tumors and related cells simultaneously. Cancer-associated fibroblasts (CAFs) are crucial stromal cells within the tumor microenvironment (TME), making them potential targets for therapy. Previously, we found that the CB1 receptor agonist ACPA has anti-tumor effects on NSCLC, inhibiting pathways such as Akt/PI3K, JNK, glycolysis, the citric acid cycle, and the urea cycle both in vitro and in vivo. We hypothesize that ACPA could enhance therapy by inhibiting the transformation of lung fibroblasts into CAFs via exosomes. Control and ACPA-treated NSCLC cell exosomes exhibited similar size, PDI, ZP, and high expression of CD9, CD63, and CD81. ACPA-treated exosomes showed reduced levels of miR-21 and miR-23. These exosomes decreased fibroblast viability within 12 h by disrupting pentose phosphate, lipid, and amino acid metabolism, and by lowering PDPN, α-SMA, and FAP expressions. This research highlights ACPA as a promising chemotherapeutic agent, capable of improving NSCLC treatment and reprogramming the TME with more targeted therapies.