Manipulation of the tumor immuno-microenvironment via TAM-targeted expression of transcription factors.

An immunosuppressive tumor microenvironment (TME) leads to cancer growth, metastasis, and therapeutic resistance. Immunomodulatory immunotherapy aims to skew the immunosuppressive TME back to an immune active state. Tumor-associated macrophages (TAMs) are a critical component of the TME that are actively involved in tumor-specific inflammation and immunosuppression. TAMs exhibit a diverse range of phenotypes and functions, from pro-tumor to anti-tumor. The plasticity of TAMs makes them a promising target for immunotherapy, and TAM-targeted therapies via different strategies have shown great potential. This review discusses current TAM-specific delivery targets and genes of interest for TAM-reprogramming. As phagocytic cells, TAMs have several receptors that have been used to increase TAM-targeted in vivo delivery. Furthermore, a promising approach for reprogramming TAMs is to activate or suppress specific transcription factors in the signal transducers and activators of transcription (STAT) and interferon regulatory factor (IRF) families. Altering TAM transcription factor expression results in a potent shift in cytokine expression and overall TAM function potentially tipping the balance from an immunosuppressive to an immune active TME.