Table 2 The possible microenvironmental sensitization biomarkers and targets synergistic with ferroptosis inducers and sensitizing mechanisms
Synergistic sensitization targets | Microenvironmental factors | Mechanisms |
|---|---|---|
CD36 and HIFs | Lipids, PUFAs, and hypoxia | Suppression of CD36 expression decreases ferroptosis sensitivity of anti-tumor T cells and destroys mitochondria fitness of Treg. HIFs antibody prevents pro-tumor polarization of TAMs and facilitates M2-type TAMs ferroptosis by affecting iron metabolism [153, 154]. CD36 and HIFs have a synergistic effect [195, 196]. |
HCAR1and MCT1 | Lactic acid | The abundant lactic acid in the TME is taken in cancer cells by transporters HCAR1 and MCT1. It activates the AMPK pathway to produce more anti-ferroptosis MUFAs, and a high level of lactic acid also inhibits the expression of ACSL4 [138, 245]. |
Gln/system Xc− | Glucose, Gln and Cys | Gln metabolism antagonizes the antioxidation function of system Xc−. Cys-deprivation triggers the death of cancer cells with extensive expression of system Xc−. Conversely, CDI ferroptosis occurs in cancer cells with low expression of system Xc− [109]. |
E-cadherin | Cancer cell interaction | Interaction of cancer cells promotes the expression of E-cadherin to activate the Hippo pathway, inhibiting the expression of ANGPTL4, TFRC, and ACSL4 and the production of ROS to maintain resistance to ferroptosis [160, 162]. |