Abstract

Tumor metastasis is facilitated by the formation of the premetastatic niche (PMN) in destination organs and the dissemination of cancer cells detached from a primary tumor. This study reports a sequential combination strategy that exerts a profound anti-metastasis effect by inhibiting both PMN formation and cancer cell dissemination. The approach consists of (1) cancer-associated fibroblast cells (CAFs)-targeting liposome and (2) mitochondria-targeting polymer. The liposome depletes CAFs and reduces tumor stroma, leading to a significant increase in intratumoral oxygen perfusion. The polymer disrupts mitochondria aerobic respiration in cancer cells, leading to a considerable decrease in intratumoral oxygen consumption. With the complementary mechanisms, their combination drastically alleviates the hypoxia in orthotopic breast tumor and inhibits the pulmonary PMN formation by downregulating various hypoxia-induced PMN-fostering factors. In addition, the CAFs depletion by the liposome abrogates the metastasis-promoting crosstalk with cancer cells; meanwhile, mitochondria dysfunction by the polymer cuts off the energy supply that supports metastasis, together resulting in an efficient suppression of cancer cell dissemination. With the two-pronged strategy targeting these two aspects, the primary tumor is prominently inhibited, and distant metastasis is completely eradicated. This study provides a generalizable approach of sequential CAFs depletion and mitochondria disruption to combat metastatic tumors.