The impact of the tumor microenvironment on macrophages

Abstract

The tumor microenvironment (TME), which has crucial roles in tumor progression, metastasis, and drug resistance, contains abundant immune cells. The most influential of these include tumor-associated macrophages (TAMs), which both secrete microenvironment-modifying cytokines and are acted upon by various other components of the microenvironment. The heterogeneity and diversity of TAMs are closely associated with patients' response to tumor immunotherapy; thus, therapeutic targeting of TAMs has become a research focus in recent years. Although numerous studies have explored how TAMs alter the microenvironment, relatively few have investigated the impact of the microenvironment on TAMs. In this review, we discuss the effects of various components of the tumor microenvironment on TAMs from the perspectives of recruitment, reprogramming, and functional modulation, with a focus on the cellular components of the microenvironment. We also summarize the development of immunotherapies targeting TAMs, which have shown promising results in clinical trials.

Keywords: functional modulation; macrophages; recruitment; reprogramming; tumor microenvironment.

Figure 1

The recruitment of macrophages by different components in the TME. This figure summarizes how various components in the TME recruit macrophages. Studies indicate that chemokines and cytokines play pivotal roles in macrophages recruitment. The molecules highlighted in red represent reported macrophage-targeting molecules (e.g., CCR2, CSF1R), which hold significant research value in tumor immunotherapy. CAF, cancer-associated fibroblasts; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CXCL, C-X-C motif chemokine ligand, CXCR, C-X-C motif chemokine receptor; CSF1R, colony stimulating factor 1 receptor; EC, endothelial cell; ECM, extracellular matrix; EP, e-type prostanoid receptor; IFN-γ, interferon-γ; IL, interleukin; MMP, matrix metalloproteinase; MDSC, myeloid-derived suppressor cell; PGE2, prostaglandin E2; ST2, stimulation expressed gene 2; TAN, tumor-associated neutrophil; TGF-β, transforming growth factor-β.

Figure 2

The reprogramming of macrophages by different components in the TME. This figure summarizes how various components in the TME affect the reprogramming of macrophages. The cellular components in the TME regulate reprogramming through cytokines and chemokines, as well as through soluble proteins, metabolites (such as lactate), EVs, etc. And the reprogramming process involves not only epigenetic regulation of critical transcription factors (such as HIF-1α), but also the activation of complement cascades (C5a/C5aR signaling axis), Similarly, the highlighted molecules refer to the reported targets for macrophages. C5aR, complement component 5a receptor; CAF, cancer-associated fibroblasts; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CSF1R, colony stimulating factor 1 receptor; EC, endothelial cell; ECM, extracellular matrix; EP, e-type prostanoid receptor; EVs, extracellular vesicles; GABA, gamma-aminobutyric acid; HIF-1α, hypoxia inducible factor 1α; IFN-γ, interferon-γ; IL, interleukin; ITGA5, integrin α5; LOXL2, lysyl oxidase like 2; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloproteinase; miRNAs, microRNAs; PGE2, prostaglandin E2; PGI2, prostaglandin I2; PTGIR, prostaglandin I2 receptor; PSGL-1, p-selectin glycoprotein ligand-1; PTEN, phosphatase and tensin homolog; ST2, stimulation expressed gene 2; TAN, tumor-associated neutrophil; TGF-β, transforming growth factor-β.

Figure 3

Various types of drugs from the perspective of the distinct impacts of the TME on TAMs. The figure shows the recruitment, reprogramming, and functional alterations of TAMs influenced by the TME. It enumerates how various TME components influence TAMs through distinct targets and highlights corresponding inhibitors, with one representative drug in clinical trials provided for each inhibitor. Notably, research on functional impacts remains limited. and certain drugs can affect more than one process, such as CSF1 inhibitors and EP4 inhibitors, that inhibit recruitment and reprogramming. A2AR, adenosine A2A receptor; ADAM8, a disintegrin and metalloprotease 8; CAFs, cancer-associated fibroblasts; CSF1R, colony stimulating factor 1 receptor; ECM, extracellular matrix; EP, e-type prostanoid receptor; HA, hyaluronic acid; LOX, lysyl oxidase; MDSC, myeloid-derived suppressor cells; mtDNA, mitochondrial DNA; NA, not applicable; PGE2, prostaglandin E2; PGI2, prostaglandin I2; PTGIR, prostaglandin I2 receptor; ST2, stimulation expressed gene 2; STING, stimulator of interferon genes; TANs,tumor-associated neutrophils. All figures are created in https://BioRender.com.