Sequentially Targeting Cancer‐Associated Fibroblast and Mitochondria Alleviates Tumor Hypoxia and Inhibits Cancer Metastasis by Preventing “Soil” Formation and “Seed” Dissemination

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.