Tumor-associated macrophages employ immunoediting mechanisms in colorectal tumor progression: Current research in Macrophage repolarization immunotherapy

Tumor-associated macrophages (TAMs) constitute the most prolific resident of the tumor microenvironment (TME) that regulate its TME into tumor suppressive or progressive milieu by utilizing immunoediting machinery. Here, the tumor cells construct an immunosuppressive microenvironment that educates TAMs to polarize from anti-tumor TAM-M1 to pro-tumor TAM-M2 phenotype consequently contributing to tumor progression. In colorectal cancer (CRC), the TME displays a prominent pro-tumorigenic immune profile with elevated expression of immune-checkpoint molecules notably PD-1, CTLA4, etc., in both MSI and ultra-mutated MSS tumors. This authenticated immune-checkpoint inhibition (ICI) immunotherapy as a pre-requisite for clinical benefit in CRC. However, in response to ICI, specifically, the MSI^hi tumors evolved to produce novel immune escape variants thus undermining ICI. Lately, TAM-directed therapies extending from macrophage depletion to repolarization have enabled TME alteration. While TAM accrual implicates clinical benefit in CRC, sustained inflammatory insult may program TAMs to shift from M1 to M2 phenotype. Their ability to oscillate on both facets of the spectrum represents macrophage repolarization immunotherapy as an effective approach to treating CRC. In this review, we briefly discuss the differentiation heterogeneity of colonic macrophages that partake in macrophage-directed immunoediting mechanisms in CRC progression and its employment in macrophage re-polarization immunotherapy.