Boyacioglu, OzgeKalali, Berfin DenizRecber, TubaGelen-Gungor, DilekNemutlu, EmirhanEroglu, IpekKorkusuz, PetekKilic, Nedret2026-02-052026-02-0520252045-232210.1038/s41598-025-29726-42-s2.0-105026256175https://doi.org/10.1038/s41598-025-29726-4https://hdl.handle.net/20.500.14411/11104Nemutlu, Emirhan/0000-0002-7337-6215; Boyacioglu, Ozge/0000-0001-5240-8209; Kalali, Berfin Deniz/0009-0005-9528-0344; Korkusuz, Petek/0000-0002-7553-3915; Gelen-Gungor, Dilek/0000-0002-2089-2590; Reçber, Tuba/0000-0001-8257-7628Non-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, alpha-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.eninfo:eu-repo/semantics/openAccessNon-Small Cell Lung CancerExosomesCancer-Associated Fibroblasts (CAFs)Arachidonylcyclopropylamide (ACPA)Tumor Microenvironment (TME)Article