Immune cells attacking a tumor with 4-1BB immunotherapy.

Unlocking the Potential of 4-1BB: A New Frontier in Cancer Immunotherapy

Lena Kashyap in Health & Wellness December 2025 • 4 min read.

"Explore how targeting the 4-1BB receptor is revolutionizing cancer treatment by boosting the body's immune response and offering hope where traditional therapies fall short."

Despite advances in understanding how tumors evade the immune system, effectively countering this evasion remains a challenge. A promising solution lies in 4-1BB (CD137; TNFRSF9), an activation-induced costimulatory molecule that plays a vital role in regulating immune responses. Targeting 4-1BB or its natural ligand, 4-1BBL, holds significant therapeutic potential for various clinical conditions, including cancer.

Extensive research has revealed that 4-1BB's anti-cancer effects stem from its ability to activate cytotoxic T lymphocytes (CTLs) and stimulate high levels of IFN-γ production. These actions are crucial for mounting a robust immune response against tumors, potentially leading to their eradication.

This article delves into the multifaceted aspects of 4-1BB-mediated anti-tumor responses, examining the underlying mechanisms and exploring future directions for this innovative approach to cancer therapy.

How Does 4-1BB Kickstart the Immune System to Fight Cancer?

Immune cells attacking a tumor with 4-1BB immunotherapy.

4-1BB, a member of the tumor necrosis factor receptor superfamily, acts as a T cell costimulatory receptor. It's triggered when T cells receive specific signals identifying an antigen (a substance that provokes an immune response). This makes it an ideal target for immunotherapy, as it enhances the body's natural ability to fight tumors in a precise, targeted manner. Clinical trials are underway, showing promising results in terms of managing toxicity.

Here's how 4-1BB signaling works:

Discovery and Phenotype: 4-1BB was identified in the late 1980s and initially referred to as induced lymphocyte activation (ILA). Although initially found in activated cells, it is constitutively expressed at low levels on Tregs and DCs. Its expression increases upon activation by cytokines, polyclonal activators, and cell surface molecules.
Biological Effects: Signals via 4-1BB are costimulatory, particularly for CD8+ T cells, which are vital for killing tumor cells. While both CD4+ and CD8+ T cells express 4-1BB, signals through 4-1BB are more effective in CD8+ T cells. In vivo, agonistic anti-4-1BB antibodies can lead to the deletion of B, NK, and CD4+ T cells while promoting CD8+ T cell expansion.
Expression on Tumor Cells: 4-1BB is expressed on a range of tumor cells, tumor vessel walls, endothelial walls, vascular smooth muscles, and liver tissue. In some instances, it can curb T cell activation and is thus considered a possible anti-tumor agent.

Given its potent effects on immune cells, 4-1BB has emerged as a strong candidate for cancer treatment. Researchers are exploring various strategies to harness its power, including monoclonal antibodies (mAbs) and combination therapies. These approaches aim to maximize the anti-tumor response while minimizing potential side effects.

The Future of Cancer Treatment: 4-1BB and Beyond

Research has demonstrated the therapeutic potential of targeting the 4-1BB pathway in cancer treatment. The capacity to eliminate established tumors is a significant advantage, and anti-4-1BB therapy can work synergistically with other anti-cancer agents or radiation therapy to eradicate non-immunogenic and weakly immunogenic tumors, further enhancing its efficacy.

Furthermore, the anti-tumor activity of ex vivo anti-4-1BB-stimulated leukocytes in adoptive cell therapy holds tremendous potential. Future studies should focus on translating anti-4-1BB therapy into clinical trials in various forms of cancer to fully leverage its anti-cancer properties.

By continuing to explore and refine 4-1BB-targeted therapies, researchers hope to unlock new possibilities for combating cancer and improving patient outcomes. As our understanding of the immune system's intricate mechanisms grows, so too will our ability to harness its power in the fight against this devastating disease.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.5483/bmbrep.2014.47.3.283, Alternate LINK

Title: 4-1Bb (Cd137), An Inducible Costimulatory Receptor, As A Specific Target For Cancer Therapy

Subject: Molecular Biology

Journal: BMB Reports

Publisher: Korean Society for Biochemistry and Molecular Biology - BMB Reports

Authors: Dass S. Vinay, Byoung S. Kwon

Published: 2014-03-31

Everything You Need To Know

What exactly is 4-1BB, and how does it target cancer cells?

4-1BB, also known as CD137 or TNFRSF9, is a costimulatory molecule that gets activated on immune cells, especially T cells, when they encounter an antigen. This activation boosts the T cells' ability to recognize and destroy cancer cells. This targeted approach aims to enhance the body's natural defenses against tumors, presenting a more precise cancer-fighting method.

How does 4-1BB signaling stimulate the immune system to destroy tumors?

4-1BB stimulates the immune system, particularly cytotoxic T lymphocytes (CTLs), to produce high levels of IFN-γ. This activation is crucial for a robust immune response capable of eliminating tumors. Monoclonal antibodies (mAbs) and combination therapies are being explored to enhance this anti-tumor response, while carefully managing potential side effects. Further research into the signaling pathways modulated by 4-1BB and the development of more specific agonists could improve the precision and efficacy of these therapies.

What are the therapeutic benefits of combining 4-1BB-targeted therapy with other cancer treatments?

Research indicates that 4-1BB's ability to eliminate established tumors makes it a valuable asset in cancer therapy. It can synergize with other anti-cancer treatments, like radiation therapy, to eradicate even non-immunogenic or weakly immunogenic tumors. Investigating the specific molecular interactions and downstream effects of 4-1BB activation in different tumor microenvironments could help refine combination strategies and predict treatment outcomes. However, how 4-1BB interacts with other costimulatory molecules, such as CD28 and OX40, in combination therapies to produce optimal anti-tumor responses isn't mentioned and is an area of ongoing research.

Can 4-1BB have any inhibitory effects on T cell activation, and how does this affect its use in cancer treatment?

While 4-1BB's primary function is to enhance the immune response against cancer, it's also expressed on various tumor cells and in tumor vessel walls, endothelial walls, vascular smooth muscles, and liver tissue. In these instances, 4-1BB can sometimes inhibit T cell activation. This dual role makes it a complex target, and researchers are still exploring how to best leverage its anti-tumor potential. The article only briefly touches upon the expression of 4-1BB on tumor cells and does not detail the mechanisms by which it might inhibit T cell activation. More research is needed to understand the context-dependent functions of 4-1BB.

Could you describe the discovery and initial characteristics of 4-1BB and its expression patterns?

4-1BB was originally identified as induced lymphocyte activation (ILA) in the late 1980s and is found on activated cells, Tregs, and DCs. Its expression increases with activation by cytokines, polyclonal activators, and cell surface molecules. It is important for costimulation, particularly for CD8+ T cells. However, the exact molecular mechanisms by which 4-1BB interacts with other signaling pathways and the precise structural elements that mediate its interactions with other proteins need to be investigated further.