Imagine cancer as a cell that has simply forgotten how to die. Strange as it may sound, that’s one of the reasons this disease can be so persistent and difficult to treat. In the human body, all cells have a kind of “internal clock” that tells them when it’s time to step aside. This happens when the cell has already fulfilled its function, becomes damaged, or its presence poses a threat to the organism. This process is not violent or accidental: it’s called apoptosis, and it’s an orderly and natural way of dying. Apoptosis is silent, clean, and leaves no residue or inflammation. It is, in a way, a dignified and necessary death.

The problem is that cancer cells, in their transformation into malignancy, disable this process. They resist death. They alter their genes, modify the signals they receive, and block the proteins responsible for executing apoptosis. It’s as if they put a lock on their off-switch. This allows them to survive even when they should self-destruct due to accumulated genetic damage or immune attack. This is what makes cancer so dangerous: not just its rapid division, but its ability to avoid death.

But the body has more than one way to deal with this. There is another form of programmed cell death called necroptosis. Unlike apoptosis, necroptosis is not silent. It’s a noisy, inflammatory, and visible form of death. When a cell undergoes necroptosis, its membrane breaks, its contents spill into the environment, and immune cells receive an alert signal. It’s like a controlled explosion that not only eliminates the harmful cell but also calls the body’s “firefighters” to investigate. This mechanism can also be useful in eliminating tumor cells, especially those that can no longer die by apoptosis.

Figure 1. DNA damage triggers apoptosis through mitochondrial signals and caspases, while TNF-α activates necroptosis via RIPK1/RIPK3/MLKL, releasing DAMPs and alerting immune cells.

Both processes, apoptosis and necroptosis, are like two paths a cell can take when its time comes. However, many cancer cells block both paths. Fortunately, scientists are learning how to find alternative routes to force them to die. One of the most promising strategies is called synthetic lethality. This idea is based on a simple but powerful principle: if the cancer cell has already lost a vital function due to a genetic mutation, then we can target another parallel function on which it now depends to survive. And when both functions fail, the cell has no escape: it dies.

A well-known example is the BRCA1 and BRCA2 genes. These genes help repair damaged DNA. In many people with breast or ovarian cancer, these functions are impaired. In such cases, if another enzyme called PARP —which also repairs DNA but by a different mechanism— is blocked, the tumor cell can no longer stay alive and dies. The amazing thing is that healthy cells, which still have working BRCA genes, can survive just fine. This means the treatment is more specific, with fewer side effects and greater effectiveness.

This approach is not limited to BRCA. Other mutated genes, such as KRAS, MYC, or even p53 (a key gene known as the “guardian of the genome”), can also be exploited for similar strategies. For example, some cancers have high MYC gene activity. These cells may be very sensitive to certain drugs that interfere with their growth, and if combined with others that block survival pathways, cell death can be induced with great effectiveness.

And here is where necroptosis comes in again. Although it is not yet widely used in the clinic, researchers are exploring how to induce it in tumors that have blocked apoptosis. There are molecules that, when administered, can activate the proteins needed to trigger this inflammatory death. It has even been shown that applying heat to a tumor —in a technique known as hyperthermia— can increase the amount of proteins that enable necroptosis. This could be useful in tumors that would otherwise be completely resistant to any kind of chemotherapy.

There’s another advantage too: when a tumor cell dies by necroptosis, its contents stimulate the immune system. This could make necroptosis an ally of immunotherapy —a boost to the body’s own defenses that are already trying to fight cancer. Some immune cells, such as dendritic cells, can recognize the cellular debris released during necroptosis and present those fragments as “danger signals” to T cells, the main killer cells of the immune system. This creates a kind of natural vaccination against the tumor —an immune memory that could help prevent relapse.

Of course, it’s not all that simple. Inducing necroptosis without control could cause excessive inflammation in healthy tissues. That’s why, before applying these strategies, it’s crucial to carefully study the genetic and molecular profile of the tumor. It must be confirmed that the tumor retains the necessary proteins for necroptosis to be activated. Not all tumors have these mechanisms intact, and in some cases, they might need a little “push” beforehand to respond properly.

Table 1. Key differences between two types of programmed cell death and their relevance in cancer.

 

What’s exciting is that this line of research is leading to a new way of thinking about cancer treatment. It’s no longer just about “killing” cells indiscriminately, but about understanding why they don’t die when they should, and how we can reactivate the body’s natural mechanisms to make that happen. It’s a more precise, more personalized, and, above all, smarter medicine.

As more targeted drugs, therapeutic combinations, and genetic tools are developed, these ideas are becoming closer to concrete treatments. We are at a point where cell death, once seen only as a problem, may actually be the solution. Teaching cancer how to die, by reawakening what was once its most basic biological function, could be the key to defeating it.

And so, instead of continuing to fight cancer from the outside, we might begin to defeat it from within. Because perhaps the real Achilles’ heel of cancer is not its uncontrolled growth…

but its inability to die like a normal cell.

 

Main Reference:

Dasgupta, A., Nomura, M., Shuck, R., & Yustein, J. (2016). Cancer’s Achilles’ Heel: Apoptosis and Necroptosis to the Rescue. International journal of molecular sciences, 18(1), 23. https://doi.org/10.3390/ijms18010023

 

Other References:

Mattson M. P. (2000). Apoptosis in neurodegenerative disorders. Nature reviews. Molecular cell biology, 1(2), 120–129. https://doi.org/10.1038/35040009

Ichim, G., & Tait, S. W. (2016). A fate worse than death: apoptosis as an oncogenic process. Nature reviews. Cancer, 16(8), 539–548. https://doi.org/10.1038/nrc.2016.58

Chen, D., Yu, J., & Zhang, L. (2016). Necroptosis: an alternative cell death program defending against cancer. Biochimica et biophysica acta, 1865(2), 228–236. https://doi.org/10.1016/j.bbcan.2016.03.003