Targeting the macrophage immunocheckpoint: a novel insight into solid tumor immunotherapy

Abstract

Tumor immunotherapy, which targets immune checkpoints, presents a promising strategy for the treatment of various cancer types. However, current clinical data indicate challenges in its application to solid tumors. Recent studies have revealed a significant correlation between the degree of immune response in immunotherapy and the tumor microenvironment, particularly with regard to tumor-infiltrating immune cells. Among these immune cells, macrophages, a critical component, are playing an increasingly vital role in tumor immunotherapy. This review focuses on elucidating the role of macrophages within solid tumors and provides an overview of the progress in immunotherapy approaches centered around modulating macrophage responses through various immune factors.

Enhancing anticancer activity of macrophages through rational drug combinations

“…T cell checkpoint inhibitors (ICIs) have transformed the therapy landscape for a number of diseases; however, only a fraction of patients with cancer receive substantial benefit from ICIs. While effective biomarkers for ICI activity remain elusive, their activity hinges on several factors, including the tumor mutation burden and the expression of tumor neoantigens, the expression of immune checkpoint proteins, intratumoral heterogeneity, and the overall immune landscape ( 1 , 2 ). Regrettably, these factors limit the activity of current ICIs targeting T cell function in many cancers.…”

“…Tumor-associated macrophages (TAMs) have emerged as critical mediators of tumor initiation, progression, and therapeutic resistance ( 1 , 4 ). Macrophages exhibit remarkable phenotypic plasticity that allows them to switch among distinct functional states in response to cytokines, tumor microenvironment cues, and cell interactions ( 1 , 4 ).…”

“…Tumor-associated macrophages (TAMs) have emerged as critical mediators of tumor initiation, progression, and therapeutic resistance ( 1 , 4 ). Macrophages exhibit remarkable phenotypic plasticity that allows them to switch among distinct functional states in response to cytokines, tumor microenvironment cues, and cell interactions ( 1 , 4 ). They were initially classified into M1 and M2 subtypes based on in vitro studies of murine macrophages, with M1 macrophages described as antiinflammatory and M2 macrophages defined as proinflammatory or protumorigenic.…”

“…TAMs can enhance neoantigen presentation through cancer cell phagocytosis, potentially boosting adaptive T cell immunity ( 1 , 4 ). This function is most strongly associated with a M1-like phenotype.…”

“…For example, an IFN-γ– and TNF-α–rich tumor microenvironment increases polarization of macrophages toward a proinflammatory M1-like phenotype. Conversely, in tumors where cancer cells secrete antiinflammatory cytokines such as IL-4, IL-10, or IL-13, macrophages are pushed toward a protumoral M2-like phenotype ( 1 ). Interestingly, although still poorly characterized, recent data have demonstrated that small-molecule drugs used to target oncogene-driven cancer cells can also trigger macrophage phenotypic remodeling through direct or indirect effects.…”