For years, many cancer treatments have been administered systemically, meaning through medications that circulate throughout the body to reach tumor cells wherever they may be. This strategy has been fundamental in oncology and remains necessary in many scenarios, especially when the disease has spread. However, it also presents an important challenge: in order to reach the tumor, the treatment must cross multiple biological barriers and distribute through various tissues, including healthy ones, which may lead to adverse effects before reaching a sufficient concentration at the site where it is most needed.
Intratumoral immunotherapy begins from a different idea: instead of waiting for the treatment to reach the tumor through circulation, it is administered directly into the tumor mass. This approach seeks to use the tumor as the main site where three key elements are found: cancer cells, tumor antigens, and the immune microenvironment that needs to be modified. In other words, treatment begins exactly where the most important interaction between cancer and the immune system takes place.
The main reason for using an intratumoral strategy is that the tumor is not simply a mass of malignant cells. It is a complex ecosystem. Inside it, there are cancer cells, blood vessels, extracellular matrix, immune cells, fibroblasts, inflammatory signals, and immunosuppressive molecules. This microenvironment can prevent the immune system from recognizing cancer, block the entry of T lymphocytes, or shut down their function once they arrive at the tumor. For this reason, it is often not enough to activate the immune system in a general way; it is also necessary to change the local conditions inside the tumor.
A simple way to understand this is to think of the tumor as a “protected territory.” Even if the immune system has cells capable of recognizing cancer, these cells may not reach the tumor site, may become trapped at the periphery, or may lose activity within a hostile environment. Intratumoral therapy seeks to intervene directly in that territory, breaking tolerance signals, increasing local inflammation, and allowing immune cells to encounter tumor antigens in a more stimulatory context.
Intratumoral administration makes it possible to concentrate the therapeutic stimulus inside the tumor. This does not completely eliminate the risk of adverse effects, but it may significantly reduce it.
Tumor Antigens: The fingerprint of cancer
Each tumor contains information about the cancer of each individual patient, including information about metastatic lesions. Proteins, DNA, and other cellular elements act as unique signals. When tumor cells die or are damaged, they can release fragments that the immune system may recognize as abnormal. These fragments, known as tumor antigens, are essential for training a specific immune response. The problem is that if these antigens are released in an immunosuppressive environment or without danger signals, the immune system may ignore them.
Turning the tumor into an “In Situ Vaccine”
The idea is not that the tumor is a vaccine by itself, but that it can become a personalized source of antigens when combined with the right immune-activating signals. By injecting immune-stimulating agents directly into the tumor, the goal is for dendritic cells to capture tumor antigens, become activated, and present that information to T lymphocytes. If this process occurs effectively, the immune response may not remain limited to the treated tumor, but could extend toward other lesions.
This possibility is one of the most interesting reasons for studying intratumoral immunotherapy. Although the treatment is applied locally, its goal may be systemic. In oncology, this is especially relevant because many patients do not have only one tumor lesion. The goal is not only to reduce the injected tumor, but to generate an immune response capable of recognizing shared characteristics among other cancer cells in the body. However, this effect does not occur in all patients and depends on multiple factors, such as tumor type, the quality of the immune response, and the degree of immunosuppression within the microenvironment.
Intratumoral immunotherapy is also important because it may help address resistance to checkpoint inhibitors. Medications such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 work by releasing immune brakes. But for these treatments to be effective, there usually needs to be a pre-existing immune response that can be amplified. If the tumor is “cold,” with low T-cell infiltration or poor antigen presentation, releasing the brakes may not be enough. In those cases, the problem is not only that the immune system is inhibited; the problem may be that it was never properly activated against that tumor in the first place.
Figure 1. Image-guided intratumoral injection delivers immunotherapy agents directly into the tumor microenvironment, where they can promote local immune activation and tumor antigen release. These signals may help train immune cells in the lymph nodes and support a systemic antitumor response capable of recognizing metastatic lesions.
Combination makes us stronger
That is where the intratumoral logic comes in: creating an initial signal within the tumor. Some intratumoral agents aim to induce local inflammation; others activate innate immune receptors, such as Toll-like receptors; others use oncolytic viruses that infect and destroy tumor cells; and others deliver cytokines or genetic material to stimulate more specific immune responses. Although these strategies differ, they share the same intention: to transform the tumor microenvironment into a space that is more visible and more vulnerable to the immune system.
A well-known example in melanoma is T-VEC, an oncolytic viral therapy administered directly into tumor lesions. There are also investigational strategies based on TLR agonists, cytokines such as IL-12, and combinations with checkpoint inhibitors. These approaches reflect a central idea: local therapy can function as an immunological spark, while systemic immunotherapy can help sustain and expand that response.
In addition, the intratumoral approach can be especially useful when combined with image-guided technologies. Many tumors are not located in the skin or in easily palpable sites. Some lesions are found in deep organs such as the liver, lung, pancreas, or internal lymph nodes. In these cases, ultrasound, CT, or other imaging techniques allow treatment to be placed more precisely inside the selected lesion. This makes intratumoral administration a strategy that is highly dependent on medical planning, tumor anatomy, and the experience of the treating team.
Of course, this strategy also has limitations. Not all tumors are accessible for injection. Not all lesions have the same microenvironment. Not all patients have enough immune capacity to generate a strong response. In addition, more studies are still needed to define which combinations are most effective, which patients benefit the most, and which biomarkers can predict response.
Even so, the question “why intratumoral?” has a clear answer: because the tumor is the place where much of the biological problem is concentrated. It contains the antigens the immune system needs to recognize. It contains many of the barriers that prevent immune response. And it is where a local signal can begin, capable of transforming a silent lesion into a site of immune activation.
Intratumoral immunotherapy should not be understood simply as a different way of injecting medication. Its value lies in changing the strategy: treating the tumor not only as a target that must be destroyed, but as an environment that can be reprogrammed. Instead of acting only from the outside, this approach attempts to modify cancer from within, using the tumor’s own biology as the starting point for a more personalized response.
In the future, the best strategies will likely not depend on a single treatment, but on rational combinations. Intratumoral activation could be combined with systemic immunotherapy, local ablation, radiation therapy, targeted therapies, or tumor microenvironment modulators. The goal will be to select the right treatment for the right patient, understanding not only the type of cancer, but also how the tumor behaves and what immune barriers it presents.
Main reference:
Hammerich, L., Binder, A., & Brody, J. D. (2015). In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf. Molecular oncology, 9(10), 1966–1981. https://doi.org/10.1016/j.molonc.2015.10.016
Other references:
Marabelle, A., Tselikas, L., de Baere, T., & Houot, R. (2017). Intratumoral immunotherapy: using the tumor as the remedy. Annals of oncology : official journal of the European Society for Medical Oncology, 28(suppl_12), xii33–xii43. https://doi.org/10.1093/annonc/mdx683
Pierce, R. H., Campbell, J. S., Pai, S. I., Brody, J. D., & Kohrt, H. E. (2015). In-situ tumor vaccination: Bringing the fight to the tumor. Human vaccines & immunotherapeutics, 11(8), 1901–1909. https://doi.org/10.1080/21645515.2015.1049779
