Reregulated mitochondrial dysfunction reverses cisplatin resistance microenvironment in colorectal cancer

Abstract Chemotherapy is one of the most basic and important treatments for malignant tumors. However, most chemotherapeutic drugs suffer from the resistance of tumor cells and lead to chemotherapy failure. Multidrug resistance (MDR) of tumor cells is the main obstacle to chemotherapy failure. The generation of MDR is not only the result of the performance of tumor cells, but the tumor microenvironment (TEM) also plays an important role in this process. The simultaneous dual intervention of cancer cells and the TEM has the potential to provide surprising results in overcoming MDR tumor therapy. Therefore, in this study, we designed a folate acid ligand‐modified nanoparticle (FA‐NPs) with a size of about 145 nm targeting multidrug‐resistant colorectal cancer and successfully co‐loaded cisplatin and Tris(2‐chloroisopropyl) phosphate (TCPP). FA‐NPs can enrich tumor sites through receptor‐mediated endocytosis. In vitro mechanism studies have shown that nanoparticles can reverse cisplatin resistance mainly by further increasing the level of reactive oxygen species in tumor cells, breaking the homeostasis of the internal environment, then trigging mitochondrial stress, regulating drug resistance‐related pathways, and improving the tumor drug resistance microenvironment; finally, the cisplatin recovers the antitumor effect with assistance from TCPP.