Why activating the immune system is not enough and what conditions make it truly effective
Immunotherapy has changed the way cancer is understood because it shifts the focus from the tumor to the immune system. Instead of thinking solely about how to destroy tumor cells, this approach starts from a broader idea: the body already has a system capable of recognizing, containing, and eliminating abnormal cells. This system does not always fail completely; in many cases, it is blocked, confused, or redirected by the tumor itself.
The real challenge, therefore, is not simply to “stimulate the defenses,” but to ensure that the immune response is specific, strong, sustained, and directed against cancer. This distinction is important. Activating the immune system in a general way may not be sufficient and can even be counterproductive if that activation is not properly directed toward the tumor. For immunotherapy to work, several conditions must align: the tumor must be visible, immune cells must be active, escape mechanisms must be blocked, and the tumor microenvironment must allow the response to occur.
Recognizing the tumor: the first step of any immune response
For the immune system to attack cancer, it must first recognize it as something abnormal. This occurs through tumor antigens, which are signals or molecular fragments associated with cancer cells. A simple way to understand them is to think of them as labels that indicate a cell is not behaving normally.
These labels must be presented to the immune system. Molecules such as the MHC (major histocompatibility complex) are involved in this process, functioning as a kind of molecular display. The cell places protein fragments on this display, and T lymphocytes inspect whether what they see appears normal or suspicious. The problem is that many tumors learn to hide these signals: they may reduce MHC expression, alter the antigens they present, or create an environment that prevents immune cells from interpreting them correctly.
For this reason, one of the major challenges of immunotherapy is to make the tumor visible. If the immune system lacks clear information, it cannot attack with precision. Dr. Jason Williams suggests that tumor ablation may help address this issue because destroying part of the tumor releases antigens that were previously hidden, allowing the immune system to “learn” to recognize cancer more effectively.
In simple terms, destroying part of the tumor not only reduces tumor burden; it can also turn the tumor into a source of immunological information. Dendritic cells, which are antigen-presenting cells (APCs), can collect these fragments, process them, and present them to T lymphocytes. It is like giving the immune system a clearer picture of the enemy.
Releasing the brakes is not always enough
One of the most important advances in immunotherapy has been the development of immune checkpoint inhibitors (ICIs). These drugs act on molecules such as PD-1, PD-L1, or CTLA-4. Under normal conditions, these molecules help prevent the immune system from attacking healthy tissues. They function as safety brakes.
The problem is that cancer can use these brakes for protection. For example, a tumor cell may express PD-L1, a ligand that binds to PD-1 on T cells and reduces their activity. In practice, the tumor is telling the lymphocyte: do not attack me. PD-1/PD-L1 inhibitors block this signal and allow the T cell to regain part of its activity.
However, releasing the brake does not guarantee movement. For a T cell to effectively attack, it must recognize the tumor, receive activation signals, physically reach the tumor site, and remain functional within a hostile environment. If any of these steps fail, the response may be weak. For this reason, modern immunotherapy cannot be thought of as a simple on/off switch; rather, it is a coordinated network of signals.
The tumor microenvironment: where many responses fail
The tumor does not exist in isolation. It is surrounded by a tumor microenvironment (TME), which includes immune cells, blood vessels, extracellular matrix, fibroblasts, inflammatory molecules, and specific metabolic conditions. This environment can either support or inhibit the immune response.
In many cancers, the TME is immunosuppressive. This means that instead of helping immune cells attack, it creates conditions that weaken them. Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) can accumulate, limiting immune activity and promoting tumor growth.
When suppressive signals dominate, effector T cells—the ones responsible for attacking—lose functionality. It is like sending soldiers into a battlefield with no oxygen, limited resources, and constant signals telling them to stop. This can lead to exhaustion and loss of function. For this reason, successful immunotherapy must not only activate immune cells but also transform the environment in which they operate, effectively turning a “cold” tumor into a “hot” one.
In immuno-oncology, a tumor is considered “hot” when it is infiltrated by active immune cells, particularly CD8+ T lymphocytes, and “cold” when there is little infiltration or when the response is blocked. “Heating” a tumor means making it more visible, inflamed, and accessible to immune attack.
The importance of acting within the tumor
One of the key ideas is that the most important place to initiate an immune response against cancer is the tumor itself. This makes biological sense. The tumor contains the antigens, the immune cells attempting to infiltrate it, the escape signals, and the barriers preventing an effective response. If the immune system is to learn what to attack, the tumor is the primary site of instruction.
Systemic immunotherapy, administered intravenously, circulates throughout the body. While useful, only a fraction of the treatment reaches the tumor. In contrast, intratumoral immunotherapy aims to concentrate therapeutic agents directly at the site where the response is needed. This localized approach can generate a strong immune response that may later extend to other tumor sites.
This concept is related to the abscopal effect, a phenomenon in which local treatment of one tumor lesion leads to regression of distant untreated tumors. This type of response has been observed more frequently when ablation techniques are combined with intratumoral immunotherapy.
The logic is straightforward: if the immune system learns to recognize cancer in one location, it can identify similar cells elsewhere in the body. Thus, a local intervention can become systemic.
Hypoxia, acidity, and resistance: the metabolic side of the tumor
Another key principle is that tumors do not evade the immune system only through molecular signals; they also modify their physical and metabolic environment. Many tumors contain regions with low oxygen levels, known as hypoxia. These areas tend to be more resistant to treatment, promote tumor aggressiveness, and contribute to immunosuppression.
Hypoxia can activate cellular programs that allow tumor survival under stress and may hinder the infiltration and function of immune cells. Additionally, tumors often exhibit altered metabolism that leads to an acidic environment. This acidity can directly impair T cell function and favor immunosuppressive populations.
The strategy, therefore, includes identifying and targeting hypoxic regions through local procedures such as intratumoral injections or ablation.
Figure 1. The anti-tumor immune response involves a coordinated sequence of events, including antigen release, uptake by antigen-presenting cells, T cell activation, and subsequent infiltration into the tumor, culminating in tumor cell killing. This process is influenced by factors that enhance immune activity, such as therapeutic interventions and systemic immune fitness, as well as by suppressive elements within the tumor microenvironment that can hinder an effective response.
The immunotherapy pyramid: understanding the system in layers
All of this leads to a broader idea: immunotherapy does not function as an isolated intervention but as the result of multiple aligned processes. In The Immunotherapy Revolution, Dr. Jason Williams proposes conceptualizing this complexity as an immunotherapy pyramid, where each level influences the success of the next.
The logic of this pyramid is simple yet powerful. The most advanced therapies—such as checkpoint inhibitors, intratumoral immunotherapy, or complex combinations—are located at the top. These are the most visible and often the most powerful tools. However, their effectiveness depends on the biological context in which they are applied.
At the base of the pyramid are factors that determine the overall capacity of the immune system to respond. These include the gut microbiome, metabolic state, systemic inflammation, nutrition, and stress levels. Although they do not act directly on the tumor, they influence the quality of the immune response. A dysregulated or weakened immune system is unlikely to sustain an effective response, even with optimal therapeutic stimulation.
Above this base are the immunological processes that enable recognition and attack of the tumor. These include antigen presentation, T cell activation, and the balance between activating and inhibitory signals. This is where the immune system and tumor interact most directly and where many barriers arise, including immunosuppressive cells and checkpoint pathways.
At the top are therapeutic interventions, including systemic immunotherapy, intratumoral approaches, ablation, and combination strategies. Intratumoral approaches are particularly relevant because they allow direct action within the tumor microenvironment, increasing local drug concentration and enhancing immune activation at the site of interest. This local activation can subsequently expand into systemic responses.
The pyramid helps explain why the same therapy can produce very different outcomes across patients. It is not only about the drug itself, but about the state of the system as a whole. If the base is compromised or intermediate mechanisms are blocked, even a powerful intervention may have limited effects.
Thus, immunotherapy should not be understood as a single solution but as an integrated process. Its success depends on tumor visibility, immune activation, control of escape mechanisms, and the ability of the organism to sustain the response over time. Ultimately, it is this integration—rather than any single tool—that defines its true potential.
Figure 2. The immunotherapy pyramid illustrates a layered strategy to enhance anti-tumor immune responses, where therapeutic interventions at the top depend on the modulation of underlying biological processes. These include immune regulation, tumor microenvironment conditions, angiogenesis, immune cell composition, and systemic factors such as the microbiome, all of which collectively influence the effectiveness of cancer immunotherapy.
Main reference:
Jason R. Williams, 15 Oct 2019, The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients’ Lives, https://williamscancerinstitute.com/the-immunotherapy-revolution
