No abstract

Ferroptosis, a newly discovered iron-dependent cell death pathway, is characterized by lipid peroxidation and GSH depletion mediated by iron metabolism and is morphologically, biologically and genetically different from other programmed cell deaths. Besides, ferroptosis is usually found accompanied by inflammatory reactions. So far, it has been found participating in the development of many kinds of diseases. Macrophages are a group of immune cells that widely exist in our body for host defense and play an important role in tissue homeostasis by mediating inflammation and regulating iron, lipid and amino acid metabolisms through their unique functions like phagocytosis and efferocytosis, cytokines secretion and ROS production under different polarization. According to these common points in ferroptosis characteristics and macrophages functions, it’s obvious that there must be relationship between macrophages and ferroptosis. Therefore, our review aims at revealing the interaction between macrophages and ferroptosis concerning three metabolisms and integrating the application of certain relationship in curing diseases, mostly cancer. Finally, we also provide inspirations for further studies in therapy for some diseases by targeting certain resident macrophages in distinct tissues to regulate ferroptosis. Facts Ferroptosis is considered as a newly discovered form characterized by its nonapoptotic and iron-dependent lipid hydroperoxide, concerning iron, lipid and amino acid metabolisms. Ferroptosis has been widely found playing a crucial part in various diseases, including hepatic diseases, neurological diseases, cancer, etc. Macrophages are phagocytic immune cells, widely existing and owning various functions such as phagocytosis and efferocytosis, cytokines secretion and ROS production. Macrophages are proved to participate in mediating metabolisms and initiating immune reactions to maintain balance in our body. Recent studies try to treat cancer by altering macrophages’ polarization which damages tumor microenvironment and induces ferroptosis of cancer cells. Open questions How do macrophages regulate ferroptosis of other tissue cells specifically? Can we use the interaction between macrophages and ferroptosis in treating diseases other than cancer? What can we do to treat diseases related to ferroptosis by targeting macrophages? Is the use of the relationship between macrophages and ferroptosis more effective than other therapies when treating diseases?

Microenvironmental signals determine the differentiation types and distinct functions of macrophages. Tumor-associated macrophages (TAM) constitute major infiltrates around solid tumor cells and accelerate tumor progression due to their immunosuppressive functions. However, the mechanisms through which tumor microenvironment modulates macrophages transition are not completely elucidated. Hyaluronan (HA), a prominent component in tumor microenvironment, is a notable immunoregulator and its high level is often related to poor prognosis. Herein, we found that the number of M2 macrophages was highly correlated with HA expression in tumor tissues from breast cancer patients. Experimental data showed that breast cancer-derived HA stimulated M2-like TAM formation in a mouse model and had multiple effects on macrophages transformation in vitro, including upregulating CD204, CD206, IL-10 and TGF-β, activating STAT3 signal, and suppressing killing capacity. These data indicate that HA derived from breast cancer activates macrophages in an alternative manner. Further mechanism study revealed that HA-CD44-ERK1/2-STAT3 pathway served as an important regulator in M2-like TAM formation. Therefore, targeting TAM by abrogating HA-CD44 interaction may be a potential strategy for breast cancer immunotherapy.

Salmonella selectively colonizes into the hypoxic tumor region and exerts antitumor effects via multiple mechanisms, while the tumor colonized Salmonella recruits host neutrophils into the tumor, presenting a key immunological restraint to compromise the Salmonella efficacy. Here, we develop a combinatorial strategy by employing silver nanoparticles (AgNPs) to improve the efficacy and biosafety of Salmonella. The AgNPs were decorated with sialic acid (SA) to allow selective recognition of L-selectin on neutrophil surfaces, based on which the tumor-homing of AgNPs was achieved by neutrophil infiltration in the Salmonella colonized tumor. The tumor-targeting AgNPs exert the functions of (1) local depletion of neutrophils in tumors to boost the efficacy of Salmonella, (2) direct killing tumor cells via L-selectin-mediated intracellular delivery, and (3) clearing the residual Salmonella after complete tumor eradication to minimize the side effects. With a single tail vein injection of such combination treatment, the tumor was eliminated with high biosafety, resulting in a superior therapeutic outcome.