Hydroxychloroquine Platinum(IV) Conjugate Displaying Potent Antimetastatic Activities by Suppressing Autophagy to Improve the Tumor Microenvironment

Protective autophagy is a promising target for antitumor drugs exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI of 44.2% against 4T1 tumors in vivo and possessed rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with inhibition rate of 49.6%, which was obviously more potent than CDDP (21.6%). Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of autophagy inhibitor HCQ endowed platinum(IV) complex with potent autophagy impairing properties by perturbing lysosomal function in tumor cells, which promoted apoptosis synergistically with the DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting immune checkpoint PD-L1, and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.