Ursodeoxycholic\nAcid Platinum(IV) Conjugates as Antiproliferative\nand Antimetastatic Agents: Remodel the Tumor Microenvironment through\nSuppressing JAK2/STAT3 Signaling

Tumor microenvironment (TME) is a pivotal factor driving\nthe tumor\nmetastasis and leading to the failure of tumor therapy. Here, a series\nof ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling\nthe TME through suppressing JAK2/STAT3 signaling was developed. A\ncandidate was screened out, which displayed potent antiproliferative\nand antimetastatic performance both <i>in vitro</i> and <i>in vivo</i>. It displayed superior pharmacokinetic properties\ncompared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated\napoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The\nJAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited,\nand pro-death autophagy was subsequently promoted. The inflammatory\nand hypoxic TME was suppressed by downregulating COX-2, MMP9, and\nHIF-1α, which resulted in inhibited angiogenesis in tumors by\ninhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive\nTME was reversed by blocking the immune checkpoint PD-L1, further\nimproving the density of CD3<sup>+</sup> and CD8<sup>+</sup> tumor-infiltrating\nlymphocytes, and promoting macrophage polarization from M2- to M1-type.