Iron’s Hidden Weakness: A New Path in Cancer Treatment

Cancer has long challenged our best efforts in medicine; many tumors are stubbornly resistant to treatments such as chemotherapy or radiation. Despite decades of research, a significant number of tumors still elude successful treatment and intervention—especially with a rise in cancer cases. In the fast-evolving field of cancer treatment, new discoveries continuously reshape our strategies against this formidable disease. One of the latest breakthroughs in the last decade is using ferroptosis, a unique, iron-dependent cell death process revolutionizing our approach to tumor resistance in conventional treatments.      

Ferroptosis is a regulated form of cell death. Unlike traditional programmed cell death such as apoptosis, ferroptosis doesn’t follow an orderly cell death sequence but instead takes advantage of the metabolic weakness of certain cells—especially cancer cells. The body uses ferroptosis to eliminate damaged or dysfunctional cells burdened by oxidative stress, a state where an imbalance between harmful molecules and protective antioxidants leads to cell damage. Ferroptosis is triggered by the accumulation of excess iron, resulting in a process known as lipid peroxidation. Many cancer cells acquire an overload of iron due to their demand for growth. This excess iron catalyzes the production of reactive oxygen species, which are highly unstable molecules that oxidize the lipids on the cell membrane. When these lipids are oxidized, they gain oxygen atoms that disrupt the structure of the membrane and ultimately compromise its integrity, triggering cell death.

Current research on ferroptosis for cancer treatment is targeted towards developing drugs that can induce it. One approach is to use small molecule inducers or chemical compounds to promote the ferroptosis process. For example, erastin is a chemical compound that blocks the cystine/glutamate antiporter, a crucial transporter for importing cystine into the cell. Cystine is important to the cell because it's a chemical needed to produce glutathione, a powerful antioxidant that acts like a shield against damaging molecules and ultimately protects it from oxidative damage. Without this molecule, the cell cannot counteract the reactive oxygen species, ultimately leading to lipid peroxidation and cell death. Similarly, RSL3 is a compound that deactivates an enzyme called GPX4, which normally prevents cell damage by inhibiting destructive lipid peroxides. When GPX4 is inhibited, the cell is pushed towards ferroptosis due to the accumulation of lipid peroxides. 

Another approach to induce ferroptosis is the use of nanotechnology to deliver natural substances that trigger the deadly process. Natural substances with ferroptosis-inducing properties and small molecule inducers are being paired with nanotechnology delivery systems to trigger ferroptosis more precisely. Some of these compounds include dihydroartemisinin and artesunate, which are derived from the sweet wormwood plant and  the medicinal plant Withania somnifera. Nanocarriers can be made from polymers that remain stable at the neutral pH of healthy tissues but break down in the acidic pH found in tumor environments. Other examples of nanocarriers include those made to accept H+ ions, which change the charge and thus solubility or structure of the nanocarrier. These nanocarriers are engineered to hold onto their payload in normal cell environments and release it in acidic environments in which tumor cells are common. This not only provides a more precise delivery but also ensures that the side effects on healthy cells are minimized. 

In cancer models, the therapeutic application of ferroptosis inducers has shown impressive results. Studies demonstrate that combining ferroptosis inducers with traditional treatments, such as chemotherapy, results in a reduction in tumor volume by 35 to 50 percent in chemoresistant cancers. Moreover, innovative delivery systems—like acidity-activatable nanoparticles for RSL3—have been found to significantly increase positive ferroptosis and inhibit tumor growth.

Although the future of ferroptosis is promising, there are current obstacles we must overcome. For example, it is critical that ferroptosis-inducing agents and transporters are applied precisely so that normal tissues and cellular processes remain unaffected. Further trials and tests are also needed to ensure optimal dosing and efficiency in a diverse patient population.

Ferroptosis is a promising mechanism in our battle against cancer. Researchers are slowly paving the way for new treatments that may overcome tumors resistant to traditional treatments such as turning a cancer cell’s own demand into a vulnerability. While hurdles are present—as they inevitably are—the steady progress signals a promising treatment. We are building a future where even the most tenacious diseases can be overcome—one step at a time.