Abstract
The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.
Highlights
The metabolic signature of the microenvironment is responsible for the development of the immunosuppressive nature of tumors. This is mainly associated with the polarization of T cells towards a T regulatory phenotype (Treg), which promotes T cell anergy and exhaustion as well as the production of anti-inflammatory cytokines and expression of immune checkpoints such as programmed cell death protein 1 (PD-1)
oxidative phosphorylation (OXPHOS) was increased in glucose-6-phosphate isomerase (GPI) knockout cells and these cells to under normoxic conditions,ofwhile hypoxia
Lactate is produced by the hypoxia inducible factor (HIF)-target lactate dehydrogenase (LDH)
Summary
Tumors are characterized by the development of an adequate milieu, including factors and conditions that are necessary for tumor development and progression. The metabolic signature plays a crucial role in MΦ polarization, including the level of fatty acid oxidation [19], hypoxia inducible factor (HIF)-1α activation, iron availability, or lactate exposure [20] The combination of these signals within the complex tumor scenario makes the polarization of TAMs a dynamic process [21]. The metabolic signature of the microenvironment is responsible for the development of the immunosuppressive nature of tumors This is mainly associated with the polarization of T cells towards a T regulatory phenotype (Treg), which promotes T cell anergy and exhaustion as well as the production of anti-inflammatory cytokines and expression of immune checkpoints such as programmed cell death protein 1 (PD-1). A better understanding of the metabolic needs, and the metabolic turnover of both tumor cells and infiltrating immune cells, is urgently needed to efficiently adapt cancer therapy
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