Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities

Abstract

Tumor-associated macrophages (TAMs) are a heterogeneous population that play diverse functions in tumors. Their identity is determined not only by intrinsic factors, such as origins and transcription factors, but also by external signals from the tumor microenvironment (TME), such as inflammatory signals and metabolic reprogramming. Metabolic reprogramming has rendered TAM to exhibit a spectrum of activities ranging from pro-tumorigenic to anti-tumorigenic, closely associated with tumor progression and clinical prognosis. This review implicates the diversity of TAM phenotypes and functions, how this heterogeneity has been re-evaluated with the advent of single-cell technologies, and the impact of TME metabolic reprogramming on TAMs. We also review current therapies targeting TAM metabolism and offer new insights for TAM-dependent anti-tumor immunotherapy by focusing on the critical role of different metabolic programs in TAMs.

Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression

“…However, it is widely accepted that this binary classification of macrophages on anticancer M1 and pro-cancer M2 is oversimplified and can be seen only in vitro as a result of stimulation of activated monocytes with bacterial LPS/IFNγ or IL-4. Single cell RNA sequencing data indicate that TME is enriched by TAMs, expressing both M1 and M2 markers under the effect of tumor producing signaling molecules and different environmental factors in the TME, such as hypoxia and acidosis (effect of hypoxia and acidosis is discussed in Section 2 of this review) [12,13]. At the first stage of the tumor development activity of M1 macrophages, in particular, increased levels of ROS, NO, and the active inflammation process help them to destroy tumor cells, But as the tumor progresses and produces recruiting and polarization factors, such as IL-34, colony stimulating factor 1 (CSF1), M2-like macrophages start to predominate in the TME, which prohibit anticancer response and promote tumor growth and progression, contributing to proliferation and migration of cancer cells, angiogenesis, and metastasis (see Section 3 of this review).…”

Recent advances in understanding the immune microenvironment in ovarian cancer

“…While CD8+ or cytotoxic T lymphocytes (CTLs) target tumor cells for destruction, regulatory T cells (Tregs) suppress the activity of effector T cells and promote immunosuppression within the TME ( 37 – 39 ). M1-type macrophages typically release Th1 cytokines, exerting pro-inflammatory and anti-tumor effects ( 40 , 41 ). However, TAMs in the TME predominantly exhibit the M2 subtype and can induce angiogenesis and tumor invasion by secreting Th2 cytokines ( 42 , 43 ).…”