Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling

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