Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy

Abstract

Ferroptosis is a recently recognized form of non-apoptotic regulated cell death and usually driven by iron-dependent lipid peroxidation and has arisen to play a significant role in cancer biology. Distinct from other types of cell death in morphology, genetics, and biochemistry, ferroptosis is characterized by the accumulation of lipid peroxides and lethal reactive oxygen species controlled by integrated oxidant and antioxidant systems. Increasing evidence indicates that a variety of biological processes, including amino acid, iron, lactate, and lipid metabolism, as well as glutathione, phospholipids, NADPH, and coenzyme Q10 biosynthesis, are closely related to ferroptosis sensitivity. Abnormal ferroptotic response may modulate cancer progression by reprogramming the tumor microenvironment (TME). The TME is widely associated with tumor occurrence because it is the carrier of tumor cells, which interacts with surrounding cells through the circulatory and the lymphatic system, thus influencing the development and progression of cancer. Furthermore, the metabolism processes play roles in maintaining the homeostasis and evolution of the TME. Here, this review focuses on the ferroptosis-mediated crosstalk in the TME, as well as discussing the novel therapeutic strategies for cancer treatment.

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment

“…In detail, the resulting metabolic activity (i.e., enhanced aerobic glycolysis), blood flow dysfunction, and inflammation lead to TME disorder, which can be described as hypoxia, acidity, nutrient deprivation, electrolyte imbalance, and elevated oxidative stress . TME-based therapy targeting vascular abnormalities, hypoxia, pH, immune response, and extracellular enzyme might modulate TME, thereby improving therapeutic effectiveness. , As described above, TME is reported to exert an effect on regulating ferroptosis, and the ferroptosis of cancer cells is described to remold TME in turn. , Therefore, TME-triggered ferroptosis nanotherapeutics might be a potent strategy for defeating drug resistance of tumors, which is an obstinate problem in almost all therapies.…”

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

“…In this scenario, Fe 2+ might sustain TAMs and TANs in supporting cancer progression and impairing T and B cell activity by inducing cell death. Fe 2+ has been involved in the induction of ferroptosis by mechanisms that are still poorly understood [100]. Although the impact of Fe 2+ secretion by TAMs and TANs is not directly proven, it is likely that high Fe 2+ levels may contribute to the induction of ferroptosis in T cells and cancer cells.…”

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

“…Lactic acid as a glycolytic metabolite has been shown to be a negative regulator of ferroptosis ( Zhao et al, 2020 ). Lactic acid can induce the formation of monounsaturated fatty acids through the HCAR1/MCT1-SREBP1-SCD1 pathway and resist oxidative stress-induced ferroptosis in hepatocellular carcinoma (HCC) cells ( Zhao et al, 2020 ; Liu et al, 2021 ). It has been suggested that the rerouting of tumour cell metabolism from glycolysis to OXPHOS could make cells more vulnerable to GSH depletion and ferroptosis ( Ždralević et al, 2018 ).…”