For a long time, drug development followed an almost mechanical logic: one disease, one molecular target, one molecule designed specifically to attack it. However, biology is rarely that orderly. The same pathways that regulate inflammation can influence cellular proliferation; those that control energy metabolism can determine lymphocyte activation. Nature constantly reuses mechanisms. Medicine, gradually, has begun to do the same.
When researchers identify that a drug approved for one condition might be useful in a completely different one, they are not improvising. They are recognizing that biological pathways do not belong exclusively to a single disease. This strategy, which consists of studying existing medications for new therapeutic indications, is known as drug repositioning. More than a shortcut, it is an intelligent reinterpretation of accumulated knowledge: if we already understand how a molecule interacts with certain cellular pathways, we can ask in which other contexts those same pathways are relevant.
In oncology, this idea gains particular strength because cancer is not simply a group of cells growing uncontrollably. It is an ecosystem. The tumor modifies its surroundings, recruits protective cells, alters local metabolism, reshapes inflammatory signals, and builds a microenvironment that limits immune activity. It does not merely defend itself; it reorganizes the battlefield.
This is where some common medications acquire new meaning.
Aspirin, for example, inhibits COX-1 and COX-2 enzymes, reducing the production of prostaglandin E2 (PGE2). In the tumor context, PGE2 is not merely an inflammatory molecule; it acts as a kind of biochemical curtain that limits immune visibility. It decreases interferon production, interferes with dendritic cell maturation, and favors the expansion of immunosuppressive populations. When that signal is reduced, the tumor does not instantly disappear, but it is as if part of the fog shielding it begins to dissipate, allowing immune cells to better distinguish their target.
Metformin, widely used in type 2 diabetes, works by activating AMPK and inhibiting mTOR, a crucial pathway in cellular metabolism. Tumor cells rely heavily on adapted metabolic pathways to sustain their accelerated growth. If we imagine the tumor as a factory that never shuts down its machinery, mTOR would be one of the main switches keeping everything running at full capacity. By modulating that pathway, metformin does not destroy the structure, but it may reduce the intensity of its operations, affecting both tumor proliferation and the metabolic state of surrounding immune cells.
Something similar occurs with PDE-5 inhibitors. These drugs, known for other indications, can reduce the activity of myeloid-derived suppressor cells (MDSCs). These cells limit T cell activation by degrading arginine, an amino acid essential for their function. Without sufficient arginine, lymphocytes cannot fully activate. In practical terms, it is as if immune cells arrive at the battlefield with their fuel tanks partially empty. By decreasing MDSC activity, it becomes more likely that this metabolic “fuel” remains available, allowing the immune response to regain part of its strength.
Sitagliptin, a DPP-4 inhibitor, also reveals interesting connections. DPP-4 degrades chemokines such as CXCL10, which participate in recruiting T lymphocytes to the tumor site. When that signal is rapidly degraded, immune cell migration can be limited. By inhibiting DPP-4, that signal persists longer, increasing the likelihood that lymphocytes find the tumor tissue. It is as though the message indicating “this is where the problem is” remains active long enough for reinforcements to arrive.
Statins, meanwhile, interfere with the mevalonate pathway, which is involved in the synthesis of molecules necessary for multiple cellular processes. This pathway contributes to intracellular signaling and proliferation. Reducing its activity may impact both tumor growth and certain immunological dynamics. Rather than producing a dramatic and direct effect, what occurs is a subtler modification of the metabolic environment in which the tumor thrives.
Zoledronic acid, used in bone metastases, also influences this same pathway and may affect the polarization of tumor-associated macrophages. Macrophages are not inherently “good” or “bad”; their behavior depends on the signals they receive. Within the tumor microenvironment, many adopt a profile that favors growth and immunosuppression. Modifying those signals can alter their function, shifting the balance within the tumor milieu.
Figure 1. Complementary strategies aimed at converting an immunosuppressive tumor microenvironment into one that is more permissive to antitumor immunity. The interventions depicted target inflammatory, metabolic, and myeloid regulatory axes that influence T-cell infiltration, activation, and persistence within the tumor. Collectively, these approaches seek to enhance immune surveillance and improve responsiveness to immunotherapeutic strategies.
All of this becomes even more relevant when discussing “cold” and “hot” tumors. Hot tumors show significant T cell infiltration and tend to respond better to immunotherapy. Cold tumors, by contrast, display limited immune presence and a predominance of suppressive signals. Many cancers resistant to checkpoint inhibitors fall into this latter category. In such cases, the challenge is not simply to further stimulate the immune system, but to transform the environment so that such stimulation can actually be effective.
Drug repositioning does not imply that these medications are established cancer treatments or that they function independently as definitive solutions. Most data come from preclinical studies or early-phase trials. Moreover, effects depend on dosage, therapeutic combinations, tumor molecular characteristics, and the patient’s clinical status. The same medication may behave differently depending on the biological context.
For that reason, it is essential to make one point absolutely clear: the fact that a drug shows immunomodulatory potential in research does not mean it should be used independently to prevent or treat cancer. Self-medication can lead to significant adverse effects, interfere with established oncologic treatments, or alter clinical outcomes. Only rigorous clinical trials can determine safety, efficacy, and appropriate combinations. Any therapeutic decision must be evaluated by a healthcare professional who considers the patient’s individual situation.
The true value of drug repositioning does not lie in finding shortcuts, but in understanding that diseases share interconnected biological networks. In cancer, where the tumor microenvironment is as decisive as the malignant cell itself, reinterpreting known medications from a new perspective may open strategic therapeutic possibilities. It is not about hidden magic on a pharmacy shelf, but about biology understood more deeply.
Main reference:
Williams, J. R. (2019). The immunotherapy revolution the immunotherapy revolution: The best New Hope for saving cancer patients’ lives. Independently Published.
