Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO

Abstract

Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro- and antitumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS-derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment. This review summarizes the classical physiology of macrophages and polarization, iNOS activities, and evidence towards TAM reprogramming with current information in glioblastoma and melanoma models, and the immunomodulatory and therapeutic options using iNOS or NO-dependent strategies.

Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers

“…Thus, macrophages have emerged as a promising therapeutic target in the field of new cancer treatments due to their strategic involvement in the TME. Because of their great plasticity, macrophages can be reprogrammed according to specific signals in order to pass from a pro-tumor phenotype to an anti-tumor one, and then to oppose cancer progression [ 29 , 60 , 70 ]. Therefore, we aimed to confirm the macrophages plasticity with our polarization model and found an upregulation of M1 markers in M2 treated macrophages.…”

“…Finally, we aim to examine the plasticity of our polarized macrophages from a perspective to study new drugs that reprogram M2 macrophages to an M1 phenotype. These findings open the way to new therapeutic strategies by targeting the pathways involved in both cancer cells death and in the immune system [ 29 ].…”

Signal Pathways Involved in the Interaction Between Tumor-Associated Macrophages/TAMs and Glioblastoma Cells

“…In reaction to the altered metabolic profile of TME, TAMs evolve toward a cellular state which prioritizes utilizing glycolysis, fatty acid synthesis (FAS), and glutamine-glutamate metabolism ( 96 , 97 ), influencing TAMs recruitment and polarization. Reciprocally, these functionally reprogrammed TAMs secret a wide range of altered cytokines and angiogenic factors contributing to tumor growth and survival ( 98 – 100 ). Won et al.…”

Non-Coding RNAs Implicated in the Tumor Microenvironment of Colorectal Cancer: Roles, Mechanisms and Clinical Study

“…Macrophages are generally considered as the most common leukocytes in TME, which can be divided into M1-like macrophages (M1 macrophages) and M2-like macrophages (M2 macrophages) ( 47 ). Macrophages in TME are usually called tumor-associated macrophages (TAMs) ( 48 ) and most of them are M2-like ( 49 ). Programmed tumor cells can secrete mediators to activate tumor-associated macrophages ( 50 ).…”