Abstract
Macrophages are a major component of the tumor microenvironment and orchestrate various aspects of immunity. Within tumors, macrophages can reversibly alter their endotype in response to environmental cues, including hypoxia and stimuli derived from other immune cells, as well as the extracellular matrix. Depending on their activation status, macrophages can exert dual influences on tumorigenesis by either antagonizing the cytotoxic activity immune cells or by enhancing antitumor responses. In most solid cancers, increased infiltration with tumor-associated macrophages (TAMs) has long been associated with poor patient prognosis, highlighting their value as potential diagnostic and prognostic biomarkers in cancer. A number of macrophage-centered approaches to anticancer therapy have been investigated, and include strategies to block their tumor-promoting activities or exploit their antitumor effector functions. Integrating therapeutic strategies to target TAMs to complement conventional therapies has yielded promising results in preclinical trials and warrants further investigation to determine its translational benefit in human cancer patients. In this review, we discuss the molecular mechanisms underlying the pro-tumorigenic programming of macrophages and provide a comprehensive update of macrophage-targeted therapies for the treatment of solid cancers.
Highlights
Tumors are complex tissues where cancer cells maintain intricate interactions with their surrounding stroma
Macrophages are a major component of solid cancers and can promote tumorigenesis by facilitating angiogenesis, immunosuppression, invasion, and metastasis
Strategies aimed at targeting tumor-associated macrophages (TAMs) have shown success in clinical trials and include macrophage depletion, modifying macrophage recruitment, and the reprogramming of macrophages away from an activated M2” (AAM) endotype
Summary
Tumors are complex tissues where cancer cells maintain intricate interactions with their surrounding stroma. In colorectal cancer, TAMs are predominantly polarized toward a classically activated endotype and express pro-inflammatory cytokines such as IFNγ, which activate cytotoxic CD8+ T-cell responses to promote tumor destruction [50]. Another route by which TAMs can cause the death of tumor cells involves the production of macrophage migration inhibitor factor (MIF). Co-injection of TIE2-expressing macrophages with tumor cells significantly enhanced angiogenesis [93], while therapeutic targeting of TIE2 resulted in tumor vasculature regression and inhibited the progression of late-stage, metastatic mammary tumors, and pancreatic carcinomas [94] Because these data strongly support a role for macrophages in promoting angiogenesis, inhibiting pathways involved in these processes provide a promising therapeutic approach for the treatment of cancer.
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