Immunotherapy has profoundly changed the way we view cancer treatment. Instead of attacking the tumor only from the outside, as chemotherapy or radiotherapy do, immunotherapy seeks to awaken or enhance the immune system’s natural ability to recognize and destroy cancer cells. The problem is that when these drugs are administered systemically, meaning throughout the entire body, they can also activate the immune system in healthy tissues and produce significant adverse effects. This is where an increasingly relevant idea emerges: what if we could apply immunotherapy directly inside the tumor?
Intratumoral immunotherapy consists of injecting immune-stimulating agents directly into the tumor mass. Rather than distributing the drug throughout the entire body from the beginning, the immune stimulus is concentrated in the place where the greatest amount of tumor information is found. This is important because a tumor is not just a group of malignant cells; it also contains antigens, infiltrating immune cells, blood vessels, inflammatory signals, and escape mechanisms. In other words, the tumor is a complex biological ecosystem. The proposal of intratumoral immunotherapy is to take advantage of that ecosystem and turn it into a kind of “training center” for the immune system.
The Tumor as an Immune Training Site
A simple way to understand this is to imagine that the tumor contains the “fingerprints” of cancer. Each tumor has particular proteins and signals that can distinguish it, at least in part, from normal tissues. When immune-stimulating agents are injected into the tumor, the goal is to activate immune cells that are already there or that can arrive at that site. Among them, T cells stand out because they are capable of recognizing specific antigens and attacking abnormal cells. If this activation occurs correctly, T cells could not only act within the treated tumor but also circulate throughout the body and recognize tumor cells in other locations. For this reason, the objective is not only to achieve a local effect, but also to generate a systemic and durable response.
One of the most attractive concepts behind this strategy is using the tumor as an in situ vaccine. Unlike a conventional vaccine, where an antigen must first be identified and formulated as a treatment, intratumoral immunotherapy uses the antigens already present within the patient’s own tumor. This could favor a polyclonal response, meaning a response directed against multiple tumor targets at the same time. This feature is relevant because tumors are often heterogeneous: not all their cells are the same, not all express the same markers, and not all respond to treatment in the same way. A broader immune response could help confront that internal diversity.
This approach may be especially interesting in the neoadjuvant setting, meaning before the main treatment, which is often surgery. Traditionally, neoadjuvant therapy has been used to reduce tumor size, facilitate surgery, or treat early micrometastases. But when we talk about immunotherapy, the timing of treatment may have additional value. If the tumor is still present, it functions as a rich source of antigens. This means the immune system can “see” the enemy more clearly before the tumor is surgically removed. In theory, treating before surgery could allow for a more powerful immune activation than treating afterward, when the main source of antigens is no longer present.
This idea has a strong biological logic. When the tumor remains in the body, it contains living tumor cells, dying cells, antigens, neoantigens, and immune cells that have already been in contact with that microenvironment. If immunotherapy is administered at that moment, a unique window can be used: the tumor is still available to educate the immune system. After surgery, although removing the tumor may be necessary and beneficial, that direct source of immunological information is also removed. For this reason, some preclinical studies mentioned in the paper suggest that immunotherapy administered before surgery may generate better responses than when it is administered only afterward.
Local Delivery, Lower Systemic Exposure
Another important advantage of intratumoral administration is the possibility of using high local doses with lower systemic exposure. In immunotherapy, more activation does not always mean a better result. Excessive immune activation can cause inflammation in healthy organs, autoimmune toxicity, and side effects that limit treatment. By injecting the agent directly into the tumor, the goal is to concentrate the effect where it is most needed and reduce the total amount of drug circulating through the body. This also opens the door to applying effective therapeutic combinations that could be too toxic if administered systemically.
The field includes different types of agents. Some are immune receptor agonists, such as TLR or STING agonists, which act as alarm signals to awaken innate immunity. Others are oncolytic viruses, designed to preferentially infect tumor cells and generate local inflammation. Intratumoral gene therapies are also being investigated, such as the administration of genes that encode immune-stimulating cytokines, for example IL-12. This cytokine can promote antitumor responses, activate immune cells, and stimulate interferon-gamma production. However, when administered systemically, it can be toxic; for that reason, delivering it locally inside the tumor is an attractive strategy.
Electroporation, mentioned in a previous blog, could improve the entry of certain agents into tumor cells. Electroporation uses controlled electrical pulses to temporarily increase the permeability of the cell membrane. This can facilitate the entry of genetic material or therapeutic molecules into the tumor. In clinical studies of melanoma, for example, intratumoral electroporation of a plasmid encoding IL-12 showed signs of antitumor activity, including responses in some lesions that were not directly treated. This type of result is especially interesting because it suggests that a local treatment could induce broader effects.
Figure 1. Immune-stimulating agents are delivered directly into the tumor to activate dendritic cells and prime T cells, supporting a systemic antitumor response against both primary and distant lesions.
One of the most logical therapeutic combinations is with immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4. These drugs help release the “brakes” that prevent T cells from attacking the tumor. If intratumoral therapy helps initiate or amplify the immune response within the tumor, checkpoint inhibitors could help keep that response active and functional. There is also interest in combining it with radiotherapy, since radiation not only destroys tumor cells but can also release antigens and modify the tumor microenvironment. However, the dose, number of fractions, and exact timing of radiotherapy are critical variables.
Chemotherapy may also have a more complex role than previously thought. Although for a long time it was considered mainly immunosuppressive, today we know that certain drugs, at appropriate doses and in the right contexts, can favor the immune response. Some agents may reduce immunosuppressive cells, increase antigen presentation, or induce forms of cell death that are more visible to the immune system. Therefore, the question is no longer simply whether chemotherapy “turns off” or “activates” immunity, but how it can be rationally integrated with local immunotherapy to maximize benefits and reduce antagonistic interactions.
Challenges in Reaching the Tumor
Despite its potential, intratumoral immunotherapy still faces important challenges. The first is tumor access. Not all tumors are easy to inject. Cutaneous or superficial lesions are more accessible, but deep tumors, such as pancreatic, liver, or lung tumors, require image-guided techniques, endoscopy, laparoscopy, or interventional radiology. Even so, advances in these areas have made it possible to reach many lesions that were once considered inaccessible with greater precision. The challenge is no longer only reaching the tumor, but doing so safely, reproducibly, and effectively.
Another challenge is defining the dose, schedule, and best combination of agents. Unlike systemic treatments, which are often dosed according to patient weight, intratumoral therapy may require different criteria: lesion size, tumor volume, number of treated lesions, or drug characteristics. In addition, it is not completely clear how many injections are needed, what interval is ideal, and which biomarkers should be used to measure whether the treatment is working. These questions are fundamental for moving this strategy from early clinical studies toward more standardized practice.
Technologies are also emerging that could improve the local distribution of drugs. Nanoparticles, for example, can function as vehicles to transport immunological agents, while hydrogels can act as a retaining mesh, prolonging their permanence inside the tumor, reducing systemic diffusion, and allowing the combined delivery of several stimuli. This type of pharmaceutical engineering could make intratumoral immunotherapy more precise and less dependent on repeated injections. In the future, the efficacy of this strategy will probably depend not only on the drug itself, but also on how, where, and for how long it is delivered inside the tumor.
Intratumoral immunotherapy represents a different way of thinking about cancer treatment. Although more clinical trials, better biomarkers, and more refined delivery strategies are still needed, the concept is powerful. Instead of seeing the tumor only as the enemy that must be eliminated, this approach uses it as the starting point to awaken a more intelligent, personalized, and potentially durable antitumor defense.
Main reference:
Hong, W. X., Haebe, S., Lee, A. S., Westphalen, C. B., Norton, J. A., Jiang, W., & Levy, R. (2020). Intratumoral Immunotherapy for Early-stage Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(13), 3091–3099. https://doi.org/10.1158/1078-0432.CCR-19-3642
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
Aznar, M. A., Tinari, N., Rullán, A. J., Sánchez-Paulete, A. R., Rodriguez-Ruiz, M. E., & Melero, I. (2017). Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally. Journal of immunology (Baltimore, Md. : 1950), 198(1), 31–39. https://doi.org/10.4049/jimmunol.1601145
