Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer

Interplay between breast cancer (BC) cells and the tumormicroenvironment(TME) influences the outcome of cancer treatment. Aberrant activationof signal transducer and activator of transcription 3 (STAT3) promotesthe interaction and causes immunosuppression and drug resistance.Platinum(IV) complexes SPP and DPP bearing pterostilbene-derived axialligand(s) were synthesized to inhibit the JAK2-STAT3 pathway in BCcells and regulate the TME. These complexes exerted remarkable antiproliferativeactivity against the triple-negative BC cells, suppressed the expressionof phosphorylated STAT3 and STAT3-related cyclooxygenase-2 and IL-6,and activated caspase-3 and cleaved poly ADP-ribose polymerase, preventingthe repair of DNA lesions and inducing apoptosis. Furthermore, DPPpromoted the maturation and antigen presentation of dendritic cells,repressed the proliferation and differentiation of myeloid-derivedsuppressor cells and regulatory T cells, and facilitated the expansionof T cells. As a consequence, DPP showed excellent anticancer activityagainst BC with almost no general toxicity in vivo as a potentialchemoimmunotherapeutic agent.