Adipocytes as Anticancer Drug Delivery Depot

Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses. © 2019 Elsevier Inc.Adipocytes were engineered for local delivery of anticancer therapeutics, including fatty acid and small-molecule drug. The lipolysis triggered by tumor cells promoted the release of these anticancer therapeutics. In addition, the immunogenic tumor phenotype induced by anticancer fatty acid combined with tumor-responsive doxorubicin prodrug enhanced cancer therapy. © 2019 Elsevier Inc.The tumor microenvironment composed of nonmalignant cells often promotes tumor growth by providing growth factors and preventing the infiltration of tumor-killing immune cells. It could be valuable to leverage the therapeutic potential of the nonmalignant cells within the tumor microenvironment for anticancer treatment. In this work, the adipocytes have been engineered with the encapsulation of an anticancer fatty acid and a bioresponsive doxorubicin prodrug for chemotherapy and simultaneously inducing an immunogenic tumor phenotype. These Trojan horse-like injectable engineered adipocytes can serve as a drug-delivery depot for sustained drug release with suppressed primary tumor growth and postsurgical tumor recurrence. This adipocyte-mediated drug-delivery strategy expands the scope of cell therapy and could be extended for treating other diseases associated with lipid metabolism pathways.