The immune system is especially good at recognizing and destroying cancer cells. It does this all the time, from the moment we are born until we die. However, cancer has also adapted to hide and evade this response.
Immunotherapy has changed the way we understand and treat different types of cancer. Unlike treatments that act directly on tumor cells, some immunotherapies aim to help the immune system regain its ability to recognize and respond to cancer.
Among the best known are immune checkpoint inhibitors (ICIs). Drugs targeting proteins such as PD-1, PD-L1, or CTLA-4 can block signals that limit the activity of certain immune cells, allowing the response against the tumor to become more active.
Traditionally, these drugs are administered systemically, meaning they reach the body through the circulation. However, in recent years, immunotherapeutic agents have also been administered directly into the tumor.
The difference may seem to be simply a matter of where the drug is delivered, but it can involve important aspects related to the treatment’s effects and safety.
Different routes of administration: Circulating through the body or going directly into the tumor
First, we need to understand a fundamental principle: when an immune checkpoint inhibitor is administered systemically, the drug enters the circulation and can interact with immune cells in different parts of the body.
Intratumoral administration is based on a different idea: delivering the therapeutic agent directly into a tumor lesion through probes or needles, so the effect is initially localized.
This route presents an additional challenge. Some tumors may be easily accessible, while others, located deeper in the body, may require imaging techniques such as ultrasound or computed tomography (CT) to guide the trajectory of the probe.
Dose: Administering the drug directly can allow a lower dose
When a drug is administered systemically, it must be distributed throughout the body before reaching its target. This reduces the total concentration that reaches the target and, therefore, requires a higher injected dose to compensate for this loss. It is like trying to paint a small piece of wood by throwing an entire can of paint into the air, hoping that some of the paint lands on the piece, instead of using a brush.
Intratumoral administration aims to change this relationship: instead of initially relying on circulation to reach the tumor, the drug is placed directly into it, reducing the initial dose needed to achieve the desired final dose.
A recent example comes from the randomized phase 1b NIVIPIT clinical trial, conducted in patients with metastatic melanoma. Researchers studied a combination of two ICIs: nivolumab and ipilimumab. In one group, nivolumab continued to be administered systemically, while ipilimumab was injected directly into the tumor.
To achieve an effect, the intratumoral dose of ipilimumab was ten times lower than the dose used in the group that received ipilimumab intravenously.
Although each drug has different characteristics, this demonstrates that administering an agent directly into the tumor could, in certain contexts, allow a smaller total amount of medication to be used while maintaining relevant local exposure.
Concentration: Less drug in the blood does not necessarily mean less drug in the tumor
The above also makes it clear that the goal of intratumoral administration is not simply to use less medication. The idea is to try to keep a significant proportion of it initially at the site where its effect is intended, while reducing the amount that circulates unnecessarily throughout the rest of the body.
The NIVIPIT trial provides an interesting example. The average maximum concentration of ipilimumab found in the blood was approximately 2.2 µg/mL with intratumoral administration, compared with approximately 42.2 µg/mL when administered intravenously.
In other words, systemic exposure to ipilimumab was considerably lower when it was administered directly into the tumor.
A lower dose does not necessarily aim to produce a weaker effect. The strategy attempts to change where the drug is initially concentrated and how much of it needs to circulate throughout the body.
Side Effects: Why does reducing systemic exposure matter?
Immune checkpoint inhibitors work in a very particular way. In simple terms, they help remove some of the natural “brakes” that regulate immune system activity.
This can promote a response against cancer, but it can also cause the immune system to affect healthy tissues. These reactions are known as immune-related adverse events (irAEs) and can range from mild to severe, involving organs such as the skin, intestines, liver, lungs, thyroid, and others.
For this reason, reducing systemic exposure to certain agents can be especially important.
In the NIVIPIT study, treatment-related adverse events occurred in approximately 22.6% of patients who received intratumoral ipilimumab combined with systemic nivolumab, compared with 57.1% of those who received both drugs intravenously.
The study provides clinical evidence supporting the idea that, for certain drugs and in selected patients, reducing systemic exposure through local administration could help reduce some significant adverse effects.
Immune Response: A local treatment with an objective that can extend beyond the treated tumor
At the beginning, we mentioned that one of the benefits of systemic therapy is that drugs can reach different locations, including metastatic lesions. However, the effect of intratumoral immunotherapy is not necessarily limited to the injected tumor. To understand this, we need to remember how the immune system works when destroying threats.
A tumor is not simply a mass made up of cancer cells. Within and around it are immune cells, blood vessels, molecular signals, and different types of cells that together form what is known as the tumor microenvironment.
If these immune cells are activated, they can recognize characteristics of the cancer, learn to identify them, multiply, and potentially circulate throughout the body and participate in a response against tumor cells located elsewhere.
In NIVIPIT, responses were observed both in injected lesions and in some lesions that had not been directly injected.
However, it is important not to interpret this as a guarantee that injecting one tumor will automatically cause other tumors to disappear. This response depends on many factors and remains an area of ongoing research.
Figure 1. Systemic immunotherapy circulates throughout the body, while intratumoral immunotherapy is delivered directly into the tumor, potentially allowing lower doses, higher local drug concentrations, and reduced systemic exposure.
Toward Increasingly Precise Immunotherapy
Intratumoral immunotherapy offers a different way of thinking about cancer treatment.
A tumor is not simply a mass that needs to be eliminated. It is also a biological environment where cancer and the immune system are constantly interacting. This environment can provide information and potentially become a strategic site for administering certain treatments.
Intratumoral administration of these drugs represents a strategy that aims to concentrate certain treatments where they are needed, use lower doses, and reduce systemic exposure without losing the goal of generating an immune response against cancer.
This pursuit of greater precision is one of the most interesting areas of modern immunotherapy.
This content is for educational purposes only and does not replace the evaluation or recommendations of a medical team. Intratumoral administration of immune checkpoint inhibitors remains investigational in many clinical settings, and its use should be evaluated on an individual basis.
Main reference:
Tselikas, L., Susini, S., Texier, M., Yurchenko, A., Routier, E., et al. (2026). Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1. Nature, 655(8121), 219–229. doi:10.1038/s41586-026-10341-w
Other references:
Pollack, M. H., Betof, A., Dearden, H., Rapazzo, K., Valentine, I., Brohl, A. S., Ancell, K. K., Long, G. V., Menzies, A. M., Eroglu, Z., Johnson, D. B., & Shoushtari, A. N. (2018). Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Annals of oncology : official journal of the European Society for Medical Oncology, 29(1), 250–255. https://doi.org/10.1093/annonc/mdx642
De Lombaerde, E., De Wever, O., & De Geest, B. G. (2021). Delivery routes matter: Safety and efficacy of intratumoral immunotherapy. Biochimica et biophysica acta. Reviews on cancer, 1875(2), 188526. https://doi.org/10.1016/j.bbcan.2021.188526
