The influence of biophysical niche on tumor-associated macrophages in liver cancer

Abstract

HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies.

FIGURE 1

TAM and biophysical cues in the TME of HCC. As one of the key components in the TME of HCC, TAM contributes to the establishment of the immunosuppressive microenvironment by suppressing antitumor immune responses, promoting angiogenesis and proinflammatory response to facilitate tumor invasion and metastasis, as well as drug resistance. In parallel, biophysical properties of the TME, such as increased organized fiber arrangement, matrix protein crosslinking, compressive force, substrate stiffness, and fluid shear force, show the potential to regulate the features and functional significance of TAMs. The figure is created by BioRender.com. Abbreviations: TAM, tumor-associated macrophage; TME, tumor microenvironment.

FIGURE 2

Possible biological, biochemical, and biophysical cues in TAM regulation. The phenotype and function of macrophages in the TME may be influenced by biological, biochemical, and biophysical cues. The interactions of TAM toward CAF, NK cells, B cells, hepatoma cells, CSCs, adipocytes, HSC, or hepatitis virus (HBV/HCV) serve as biological cues. The levels of nutrient supply, oxygen, cytokines, and inorganic molecules may contribute to the biochemical cues in regulating TAM. Biophysical cues refer to the surface topography, substrate stiffness, and fluid shear force. The figure is created by BioRender.com. Abbreviations: CAF, cancer-associated fibroblast; CSC, cancer stem cell; NK, natural killer; TAM, tumor-associated macrophage; TME, tumor microenvironment.

FIGURE 3

Stiffness regulates TAM features and functions in the TME of HCC. Increased ECM stiffness leads to enhanced ECM crosslinking, which is reported to regulate macrophage polarization into M2 type through mechanoreceptors such as Piezo1, TRP ion channels, and integrins. The external forces generated by stiffness could further enhance the interaction between tumor cells and TAM. The figure is created by BioRender.com. Abbreviations: ECM, extracellular matrix; TAM, tumor-associated macrophage; TME, tumor microenvironment.