For a long time, cancer was described mainly as a collection of cells growing uncontrollably, and under that view, the goal of treatment was perceived as finding those cells and destroying them. However, modern research has shown that a tumor is much more than an isolated mass. Around it exists a complex community of immune cells, blood vessels, inflammatory molecules, nutrients, supporting tissue, and chemical signals that can either promote or hinder disease progression.
This environment is known as the tumor microenvironment, and understanding it is essential because two tumors in the same organ may behave very differently depending on the cells and signals surrounding them. Some are surrounded by immune defenses capable of recognizing the cancer, but those defenses remain blocked. Others, in contrast, have barely been detected by the immune system.
Recent research published in Nature Reviews Clinical Oncology proposes that cancer therapies should be combined according to the characteristics of each tumor microenvironment. The central idea is that a single medication is unlikely to address all the mechanisms a tumor uses to grow, adapt, and escape the body’s defenses.
The relationship between cancer and the immune system
The immune system has the ability to recognize abnormal cells and eliminate them before they become a greater problem. However, this relationship is not always straightforward. As a tumor develops, cancer cells that are more easily recognized may be destroyed, while those capable of hiding or resisting the immune attack survive.
This process is known as cancer immunoediting. In other words, the immune system may initially contain tumor growth, but it can also exert pressure that favors the selection of cancer cells with more effective escape mechanisms. For this reason, cancer does not remain static: it continuously evolves and adapts.
One of its strategies is to take advantage of natural mechanisms that normally protect the body from excessive immune responses. The immune system has a series of “brakes” known as immune checkpoints. Their usual function is to prevent immune defenses from remaining active for too long or damaging healthy tissues. However, tumor cells can use these same brakes to prevent lymphocytes from attacking them.
Among the best-known immune checkpoints are CTLA-4, PD-1, and PD-L1. Medications that block these molecules can partially release the immune system’s brakes and allow lymphocytes to recover their activity against cancer. These treatments have produced durable responses in some patients with advanced diseases, but a significant proportion do not respond adequately when a single agent is used.
Why might a single immunotherapy not be enough?
A tumor can use several escape routes at the same time. For example, it may block lymphocytes through PD-L1, attract immunosuppressive cells, reduce the presentation of its antigens, limit the entry of immune cells, or create metabolic conditions that weaken their activity.
For this reason, blocking only PD-1 or CTLA-4 may solve one part of the problem while leaving other barriers intact. It would be similar to opening one door while three others remain closed. To achieve an effective antitumor response, it may be necessary to intervene in different steps in a coordinated manner.
Another challenge is that human tumors are extremely heterogeneous and adaptable. Therefore, monotherapies are unlikely to overcome all the mechanisms that suppress the immune response. Different targets may need to be attacked simultaneously, not through randomly selected combinations, but according to the biological needs of each tumor.
Four types of tumor microenvironment
To organize this complexity, researchers present a classification based on two relatively simple characteristics: the presence or absence of tumor-infiltrating lymphocytes, known as TILs, and the expression of PD-L1.
Tumor-infiltrating lymphocytes indicate that some immune defenses have managed to enter the tumor. PD-L1, meanwhile, can act as an inhibitory signal that reduces lymphocyte activity. By combining these two variables, the microenvironment can be divided into four main types.
Type I: Lymphocytes present and PD-L1 positive
In this case, the immune system has recognized the tumor, and lymphocytes have managed to infiltrate it. Nevertheless, the cancer produces PD-L1 and activates the PD-1 brake on immune cells.
This scenario is known as adaptive immune resistance. The response already exists, but it is blocked. For this reason, these tumors are often the most obvious candidates for PD-1 or PD-L1 inhibitors. The treatment does not need to create a response from scratch, but rather release a response that was already present.
Type II: No lymphocytes and no PD-L1
This type is described as an immunologically ignored tumor. The immune system does not appear to have recognized it effectively, there is no significant lymphocyte infiltration, and there is no adaptive response that would explain the presence of PD-L1.
In this situation, removing an immune brake may not be enough because there are practically no immune cells inside the tumor to reactivate. Before blocking immune checkpoints, it may be necessary to attract lymphocytes, release tumor antigens, and teach the immune system to recognize the disease.
Type III: No lymphocytes but PD-L1 positive
In this scenario, PD-L1 may be present because of the tumor’s internal characteristics and not necessarily as a response to an immune attack. Certain genetic alterations, oncogenic pathways, or conditions such as oxygen deprivation may increase its expression.
Although the tumor displays the PD-L1 brake, the absence of lymphocytes means that blocking it may be insufficient. The combination should attempt to attract immune cells into the tumor while simultaneously reducing its escape mechanisms.
Type IV: Lymphocytes present but PD-L1 negative
In this group, immune cells are present inside the tumor, but the PD-1/PD-L1 pathway does not appear to be the main mechanism blocking them. The cancer may be using other inhibitory molecules, regulatory cells, immunosuppressive macrophages, or metabolic factors.
These tumors require the identification of the true dominant brake. Other immune checkpoints, such as LAG-3, TIM-3, and TIGIT, or different signals produced by myeloid cells, may be involved. The complete classification, along with its limitations, is summarized in the article as a tool for guiding more rational combinations.
The four therapeutic fronts that could be targeted
In addition to classifying tumors, the authors propose four major therapeutic “nodes.” Each node represents an important process that can be modified to strengthen immunity against cancer.
The first node involves eliminating immune suppression. This includes immune checkpoint inhibitors, as well as strategies targeting regulatory cells, tumor-associated macrophages, and inhibitory molecules. The purpose is to remove the mechanisms that keep immune defenses switched off.
The second node seeks to induce immunogenic tumor cell death. Not every form of cell death generates an immune response. Some methods of destroying cancer release antigens and danger signals that can attract the immune system’s attention. Certain chemotherapies, radiotherapy, and targeted therapies may contribute to this process.
The third node involves improving antigen presentation. Dendritic cells and other antigen-presenting cells function as instructors of the immune system: they collect tumor fragments, display them to lymphocytes, and tell them what they should attack. When these cells do not function properly, the immune system may fail to learn how to recognize the cancer.
The fourth node seeks to activate and maintain effector cells, particularly T lymphocytes and macrophages. Identifying the enemy is not enough; immune cells must survive, multiply, enter the tumor, and retain their ability to destroy cancer cells.
The model proposes that the most effective combinations should act on several of these processes. For example, one therapy could release tumor antigens, another could improve their presentation, and a third could remove the brakes preventing lymphocytes from acting.
Combining treatments does not simply mean adding more medications
Although combinations may be more effective, they can also increase toxicity. Excessive immune activation may cause inflammation in healthy tissues, resulting in immune-related adverse effects that can affect the skin, intestines, lungs, liver, or endocrine glands.
For this reason, the question is not only how many treatments can be combined, but which treatments should be used, in which patients, in what order, and for how long. A combination that works in a type I tumor may not make sense in a type IV tumor.
Neoantigens: Each tumor’s unique signature
Every tumor accumulates mutations that can generate abnormal proteins. Some fragments of these proteins, known as neoantigens, may be recognized by the immune system as foreign elements.
The study of these neoantigens has opened the possibility of designing personalized cancer vaccines. Through genetic sequencing, researchers can identify mutations that are unique to an individual’s tumor and predict which of them may produce targets that lymphocytes can recognize.
However, a personalized vaccine is unlikely to be sufficient on its own if the tumor continues to block immune cells. It may need to be combined with immune checkpoint inhibitors, adjuvants, or treatments that promote lymphocyte entry into the tumor.
Tumor mutational burden has also been proposed as a possible biomarker, since tumors with more mutations may generate a greater number of neoantigens. Even so, not every mutation produces a useful immune response, and not every tumor with a high mutational burden responds in the same way.
Figure 1. Tumors can be classified into four microenvironment types according to the presence of T cells and PD-L1 expression. This immune landscape can help guide combination strategies aimed at removing immune suppression, inducing immunogenic tumor cell death, enhancing antigen presentation, and activating effector immune cells.
The need for more precise biomarkers
The classification based on PD-L1 and infiltrating lymphocytes provides a useful guide, but it does not represent the tumor’s full complexity. PD-L1 expression may vary between different areas of the same lesion, change over time, or be modified after treatment.
Furthermore, finding PD-L1 on cancer cells is not necessarily equivalent to finding it on macrophages or other immune cells. The value of the marker also depends on the measurement methods and the criteria used to define when a sample is considered positive.
For this reason, truly personalized immunotherapy will probably need to integrate different sources of information: genetic analyses, tumor mutational burden, protein expression, lymphocyte presence, the status of myeloid cells, the location of immune cells, and metabolic signals within the microenvironment.
Instead of asking only, “What type of cancer does this person have?” it will also be necessary to ask, “What kind of immune ecosystem surrounds the tumor?”
Toward immunotherapy designed for each microenvironment
Immunotherapy changed the way cancer is understood because it demonstrated that, under certain circumstances, the body’s defenses can control even advanced disease. However, it also made clear that there is no single solution for every tumor.
The next stage does not simply involve creating more medications, but learning how to combine them according to biological logic. To accomplish this, it is necessary to identify which barriers predominate in each tumor microenvironment and select treatments that act on those specific barriers.
Main reference:
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. (2016). Combination cancer immunotherapies tailored to the tumour microenvironment. Nature reviews. Clinical oncology, 13(3), 143–158. https://doi.org/10.1038/nrclinonc.2015.209
Other references:
Remodeling the tumor microenvironment and rational combinations in early-stage cancer immunotherapy. (s/f). Frontiersin.org. Recuperado el 5 de agosto de 2026, de https://www.frontiersin.org/research-topics/79510/remodeling-the-tumor-microenvironment-and-rational-combinations-in-early-stage-cancer-immunotherapy
