Figure 1. Strategies for Reprogramming Macrophage Phenotypes toward Defender Activity.

(A) Schematic of macrophage antitumor defender and pro-tumor remodeler phenotypes within the TME. Defender macrophages mediate antitumor activity through both direct (i.e., via phagocytosis or the release cytotoxic molecules) and indirect mechanisms (i.e., via the activation of innate and adaptive immunity). Remodeler macrophages facilitate tumor growth and progression also through direct (i.e., production of tissue invasive and angiogenic factors) and indirect mechanisms (i.e., via the secretion of immune suppressive cytokines or mediators). Reprogramming macrophages from one functional state to another is of substantial therapeutic interest, with the goal to rebalance the overall macrophage response toward a defender phenotype.

(B) Schematic of molecular targets of macrophage reprogramming agents. Efforts to reprogram macrophages toward a defender phenotype have focused on several major fronts, ranging from modifying the extracellular environment to the intracellular nuclear compartment. In addition, other approaches include targeting cell surface receptors and cytoplasmic enzymes, as shown.

(C) List of parameters for designing effective macrophage reprogramming therapies. The ability to optimally reprogram macrophages toward a defender phenotype is complex and reflects several important parameters. Several examples are illustrated, which include consideration of the relevant macrophage population(s) (i.e., TRM vs. BMDM), the platform and method of delivery of the reprogramming agent, and rational combinations with other anticancer therapies.

Created with BioRender.com