Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Abstract

Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.

Orchestrated Action of AMPK Activation and Combined VEGF/PD-1 Blockade with Lipid Metabolic Tunning as Multi-Target Therapeutics against Ovarian Cancers

“…Given that T cells are critical mediators of antitumor immunity, ferroptosis has recently been demonstrated to participate in ICIs (e.g., anti-PD-1 or anti-CTLA4)-mediated antitumor immune responses driven by cytotoxic T cells. INF-γ that is secreted from the activated cytotoxic CD8 + T cells upon ICIs blockade enhances ferroptotic effect on tumor cells by downregulating the expression of cysteine/glutamate transporter (system X C − ) subunits, SLC3A2 and SLC7A11, leading to reduced cystine uptake and subsequently enhanced lipid peroxidation and ferroptosis of the cancer cells [ 111 , 121 , 122 ] ( Figure 4 ).…”

“…Nonetheless, ferroptosis in immune cells themselves may compromise the immune responses, and there is considerable controversy as to whether ferroptosis is a two-edged sword. It has been aware that GPX4 activity is not only important for the survival of tumor cells but also plays an essential role in the development of lymphocytes [ 122 , 123 ]. Further works on T cells have revealed that deficiency of GPX4 in antigen-specific CD4 + and CD8 + T cells are unable to expand and experience ferroptotic cell death induction with an accumulation of lipid peroxides, thereby precluding their immune response to protect the host from infections [ 114 , 123 ].…”

“…However, iron addiction is one of the distinct characteristics of cancer cells that they evolve multiple mechanisms to concomitantly increase iron uptake and decrease iron export so as to ensure the iron supply for cell proliferation and aggression [ 125 , 126 ]. In addition, cancer cells with dysregulated iron metabolism can reconfigure immune cells within the TME, for example, by revising the polarization of TAMs to an anti-inflammatory phenotype associated with the augmented release of iron, leading to enhanced tumorigenesis and immunosuppression [ 122 , 127 ]. Taking into account the iron-overdosed properties around the cancerous neoplasm, ferroptosis induction promoted by delivering iron into the TME as an adjuvant may escalate cancer progression and immune evasion.…”

“…Nevertheless, barriers to ferroptosis induction on the potent antitumor immunity are not limited to these. Ferroptosis in cancer cells has been reported to be associated with strengthened secretion of immunosuppressive agents such as prostaglandin E2 (PGE2) [ 122 , 128 ], which stimulates cancer cell growth and represses cytotoxic T cell activity, inferring that further understanding of the complicated crosstalk among cancer and immune cells as well as the dual role of ferroptosis in tumor immunity is required to provide new insight on targeting ferroptosis in cancer immunotherapy.…”

“…On the other hand, AMPK is a cellular energy sensor that plays an important role in reprogramming cancer cell metabolism in various human cancers [ 23 , 131 ]. Recent results showed that system X C − inhibitors Erastin and Sulfasalazine induced the AMPK-mediated phosphorylation of Beclin 1 to form Beclin 1-SLC7A11 complex and subsequent ferroptosis initiation [ 122 , 132 , 133 ]. In contrast, metabolic proteins suppressing ferroptosis, such as BCAT2, were found to be inhibited by the AMPK/SREBP1 signaling upon treatment of ferroptosis inducers (Erastin, Sorafenib, and Sulfasalazine) in HCC cells [ 122 , 134 ], suggesting that induction of ferroptosis together with attention to cancer cell metabolism via modulation of AMPK activity may be an emerging anti-cancer strategy to combat tumors.…”