Instead of directly attacking all rapidly dividing cells, as some traditional treatments do, immunotherapy seeks to help the immune system recognize and fight tumor cells. Among its best-known tools are immune checkpoint inhibitors, drugs that target proteins such as PD-1, PD-L1, and CTLA-4.
These treatments have produced deep and lasting responses in some patients. However, many people do not respond from the beginning or experience disease progression after an initial improvement. Some studies indicate that more than half of patients may be classified as nonresponders or develop resistance after an initial response. One of the main reasons is that the tumor creates an environment around itself that can suppress immune activity.
This raises an important question: what would happen if, in addition to releasing the immune system’s brakes, treatment acted directly inside the tumor to generate a stronger alarm signal?
A tumor is more than a group of malignant cells
A tumor functions like an ecosystem. As discussed in previous blogs, it contains not only cancer cells but also blood vessels, fibroblasts, immune cells, and different molecules that can either promote or limit the response to treatment. Together, these components form what is known as the tumor microenvironment.
Some tumors contain a significant number of T cells capable of recognizing malignant cells. These tumors are commonly described as immunologically “hot.” In other cases, immune cells are scarce, remain outside the tumor, or are blocked by inhibitory signals. These tumors are often referred to as “cold.”
The problem is not always that the immune system is unable to act. Sometimes, it simply does not receive enough signals to locate the tumor, recognize its antigens, or maintain an effective response. It may also be surrounded by regulatory cells, myeloid-derived suppressor cells, and immunosuppressive cytokines that limit T-cell activity.
Immune checkpoint inhibitors attempt to release these brakes. However, removing a brake may not be enough when very few active immune cells are present inside the tumor. For this reason, intratumoral therapy and immune checkpoint inhibitors may have complementary roles.
What is intratumoral therapy?
Intratumoral therapy involves administering a therapeutic agent directly into the tumor through a needle or an image-guided procedure. The goal is not only to achieve a high drug concentration within the lesion, but also to locally modify the microenvironment and trigger an immune response.
When an agent is delivered directly into the tumor, it may promote local inflammation, release tumor antigens, activate dendritic cells, and attract immune cells. Dendritic cells act as antigen-presenting cells: they capture fragments from the tumor and display them to T cells, teaching them what they need to recognize.
In theory, the tumor can therefore become a personalized source of antigens. Instead of selecting a single tumor molecule, the immune response may be exposed to multiple targets found within the patient’s own cancer cells. This is important because tumors are heterogeneous: not all tumor cells carry exactly the same alterations.
Local administration may also allow high concentrations of the therapeutic agent within the lesion while limiting exposure throughout the rest of the body. This may be especially important for immune-stimulating agents that could cause excessive inflammation or toxicity if administered intravenously. The review highlights that intratumoral delivery may increase drug availability within the microenvironment while reducing systemic toxicity.
A two-step strategy
The logic behind this combination can be understood as a strategy of activation and maintenance.
First, intratumoral therapy acts within the lesion. It may damage tumor cells, release antigens, and generate danger signals that attract and activate immune cells. This can help transform a tumor that is poorly visible to the immune system into an inflamed and recognizable environment.
Next, immune checkpoint inhibitors block signals such as PD-1, PD-L1, or CTLA-4, which normally reduce T-cell activity. In this way, activated immune cells may maintain their function for longer and attack with greater intensity.
The local effects of intratumoral therapy can create an immunogenic microenvironment, while the systemic effects of checkpoint inhibitors can release and sustain the antitumor response.
Beyond the injected tumor
One of the most attractive possibilities is that the response may not remain limited to the treated lesion.
After recognizing tumor antigens, some T cells may circulate throughout the body and locate cells with similar characteristics in other lesions. When a local treatment produces effects in distant, untreated tumors, this is known as a systemic response or, in some contexts, an abscopal effect.
This does not mean that every intratumoral injection will automatically produce responses at distant sites. In fact, one of the major challenges in this field is achieving consistent systemic control from local immune activation.
Preclinical studies have provided encouraging signals. In animal models, combining immune agonists delivered directly into the tumor with systemic immune checkpoint blockade increased CD8 T-cell infiltration and reduced immunosuppressive cell populations. In some models, tumors that had not been directly injected also regressed. However, results obtained in animals cannot be directly applied to patients and must be confirmed in clinical trials.
What types of agents can be delivered into a tumor?
Intratumoral therapy is not a single drug. It is a platform that can use different types of agents.
Oncolytic viruses are modified or selected to preferentially infect tumor cells, destroy them, and stimulate an immune response. One of the best-known examples is T-VEC, a modified herpesvirus that produces GM-CSF and is approved for certain cases of advanced melanoma.
Toll-like receptor agonists, or TLR agonists, mimic signals that normally indicate the presence of microorganisms or cellular damage. By activating these sensors inside the tumor, they may stimulate dendritic cells, macrophages, and interferon production.
STING agonists activate a pathway that detects DNA in the cell cytoplasm. This activation may promote type I interferon production and support CD8 T-cell responses against cancer.
Researchers are also studying cytokines, messenger RNA molecules, bacterial vectors, nanoparticles, modified cells, and other immune stimulators. The review includes studies involving melanoma, sarcoma, breast cancer, glioblastoma, kidney cancer, and head and neck tumors, among others. Most of these studies are still in early phases of clinical investigation.
Promising but inconsistent results
Some clinical trials have reported meaningful response rates. Different combinations involving oncolytic viruses, cytokines, or immune agonists have shown activity in melanoma, sarcoma, and other cancers.
However, these results must be interpreted carefully. The studies differ greatly in the number of participants, cancer type, previous treatments, intratumoral agent, and systemic immunotherapy used. Directly comparing response percentages between studies may therefore be misleading.
In addition, encouraging results from small studies are not always confirmed in larger trials. An important example is the combination of T-VEC and pembrolizumab. Early research in melanoma showed promising responses, but a phase III trial involving 692 participants did not demonstrate statistically significant improvements in progression-free survival, duration of response, or overall survival compared with pembrolizumab alone.
Similarly, a TLR9 agonist called tilsotolimod showed activity in early studies, but later failed to meet its primary endpoint in a phase III trial involving melanoma resistant to anti-PD-1 therapy.
These outcomes do not invalidate the strategy. Rather, they show that not every combination works for every patient and that the choice of agent, treatment sequence, dose, and tumor context are critical.
Figure 1. Intratumoral therapies can promote tumor cell death, antigen release, dendritic-cell activation, and T-cell–mediated tumor attack, potentially helping convert an immune-cold tumor into a more immune-active hot tumor.
Challenges that still need to be addressed
Not every tumor is easy to inject. Some lesions are located near blood vessels, delicate organs, or deep anatomical structures. In these situations, the expertise of an interventional radiology team and the use of ultrasound, computed tomography, or magnetic resonance imaging may be essential.
Another decision involves selecting which lesion to treat when a patient has multiple tumors. The largest lesion is not always the best choice. Its level of necrosis, vascularization, accessibility, and immune composition may influence the response.
Accurately measuring treatment effects is another challenge. An injected lesion may become inflamed or change in size without this necessarily representing disease progression. In addition, conventional radiologic criteria do not always distinguish between the behavior of treated tumors and that of noninjected lesions. The review emphasizes the need to standardize assessments and develop biomarkers that can predict which patients are most likely to benefit.
Local reactions, the safety of repeated injections, drug distribution within the tumor, and the optimal biological dose must also be studied. In immunotherapy, the maximum tolerated dose is not always the most effective dose.
A new multimodal approach
The combination of intratumoral therapy and immune checkpoint inhibitors represents a different way of thinking about cancer treatment: acting locally to initiate the immune response and using systemic immunotherapy to expand and sustain it.
The scientific rationale is strong, but the strategy is still evolving. Some trials have shown durable responses and effects in noninjected lesions, while others have not confirmed the expected benefits in later-stage studies.
The future of this approach will depend on identifying which tumor should be injected, which agent is most appropriate, when it should be combined with immunotherapy, and which biomarkers can predict response.
Main reference:
Nelson BE, Naing A, Fu S, Sheth RA, Murthy R, Piha-Paul S. Potentiating intratumoral therapy with immune checkpoint inhibitors: shifting the paradigm of multimodality therapeutics. Immunooncol Technol. 2024 Dec 20;25:101040. doi: 10.1016/j.iotech.2024.101040. PMID: 39981134; PMCID: PMC11841068.
Other references:
Wang, M., Wang, S., Desai, J., Trapani, J. A., & Neeson, P. J. (2020). Therapeutic strategies to remodel immunologically cold tumors. Clinical & translational immunology, 9(12), e1226. https://doi.org/10.1002/cti2.1226
Hamid, O., Ismail, R., & Puzanov, I. (2020). Intratumoral Immunotherapy-Update 2019. The oncologist, 25(3), e423–e438. https://doi.org/10.1634/theoncologist.2019-0438
