Apoptosis, known as programmed cell death, is a natural mechanism that allows the body to eliminate damaged or aged cells. Under normal conditions, this process is essential for maintaining tissue balance and health. In the context of cancer, however, apoptosis plays a much more complex role. Although its activation can be useful for destroying tumor cells, it can also negatively affect immune system cells that should be fighting the tumor, especially T lymphocytes.

The tumor microenvironment—the immediate environment surrounding the tumor—is an extremely competitive and hostile space. Cancer cells not only grow uncontrollably, but also manipulate this environment to their advantage. One of the most sophisticated mechanisms they use is evasion of apoptosis. Through genetic mutations, overexpression of proteins that block cell death, and epigenetic alterations, tumor cells manage to resist therapies that would normally induce their death. This makes them formidable opponents for any conventional therapeutic strategy.

At the same time, these tumor cells compete with immune system T cells for nutrients such as glucose and amino acids. This competition prevents T cells from functioning properly: by not receiving enough energy, they weaken, become exhausted, and often die from apoptosis. In other words, the tumor not only protects itself, but also weakens the immune army trying to eliminate it.

This dynamic becomes especially relevant in the context of immunotherapy, a strategy that seeks to activate the immune system to fight cancer. Therapies such as immune checkpoint inhibitors (for example, anti-PD-1 or anti-CTLA-4) or CAR-T cells have shown promising results, but also present limitations. If T cells die or become exhausted inside the tumor, immunotherapy loses its effectiveness. Additionally, if treatments are not carefully designed, they can even accelerate the death of these immune cells through stress or overstimulation.

A recent review published in Cells (Franzese et al., 2024) emphasizes that not all forms of apoptosis have the same impact on the immune response. There are types of cell death that can stimulate the immune system—a process known as immunogenic cell death—and others that, on the contrary, promote tolerance and immunosuppression. That is why one of the major current challenges is to ensure that cancer therapies not only eliminate malignant cells but also strengthen the body’s ability to recognize and attack the tumor.

On the other hand, some conventional therapies may have unintended effects. By inducing apoptosis in tumor cells, they can also release signals that attract immunosuppressive cells, such as M2-type macrophages, which suppress the action of T lymphocytes. This can contribute to tumor recurrence or treatment resistance. In response to this, new strategies are being developed to reverse the function of these macrophages and turn them into allies of the immune system.

Figure 1. Schematic comparison of two tumor microenvironment (TME) scenarios. Left: In a TME with unbalanced apoptosis, tumor cells evade cell death via overexpression of anti-apoptotic proteins (e.g., BCL-2, survivin) and p53 disruption. High glucose uptake by tumor cells depletes nutrients from T cells, leading to metabolic exhaustion and apoptosis. Immunosuppressive M2 macrophages release TGF-β, adenosine, and PS, further inhibiting T cell activity. Right: In contrast, immunogenic cell death (ICD) triggers DAMPs (CRT, ATP, HMGB1) that activate dendritic cells and support adaptive immunity. Effector T cells induce cancer cell death through perforin/granzyme and cytokines (IFN-γ, TNF-α), promoting a robust antitumor immune response.

The clinical implications of these findings are profound. A truly effective cancer treatment cannot be limited to destroying tumor cells. It must also care for and enhance the immune system cells involved in that fight, especially those with memory capacity, which can prevent long-term relapses. To achieve this, approaches are proposed that modulate the metabolism of T cells, that use immunostimulatory instead of immunosuppressive signals, and that combine different types of therapies to achieve a more comprehensive and lasting response.

In summary, this work reminds us that apoptosis is not simply a switch that turns off harmful cells. It is a process that must be understood and precisely managed to ensure it becomes a true tool in service of the immune system and not, inadvertently, its enemy. The key lies in achieving an intelligent balance: destroying cancer without weakening the defenses that fight it.

Main Reference:

Franzese, O., Ancona, P., Bianchi, N., & Aguiari, G. (2024). Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy. Cells, 13(11), 924. https://doi.org/10.3390/cells13110924

Other References:

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660

Das, S., Shukla, N., Singh, S. S., Kushwaha, S., & Shrivastava, R. (2021). Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis : an international journal on programmed cell death, 26(9-10), 512–533. https://doi.org/10.1007/s10495-021-01687-9

Vitale, I., Pietrocola, F., Guilbaud, E., Aaronson, S. A., Abrams, J. M., Adam, D., Agostini, M., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., Aqeilan, R. I., Arama, E., Baehrecke, E. H., Balachandran, S., Bano, D., Barlev, N. A., Bartek, J., Bazan, N. G., … Galluzzi, L. (2023). Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell death and differentiation, 30(5), 1097–1154. https://doi.org/10.1038/s41418-023-01153-w