Scratching the surface

In the last decade immunotherapy has reshaped how we approach cancer treatment. Among the transformative advances in immunotherapy is chimeric antigen receptor (CAR) therapy, a technique that reprogrammes a patient’s immune cells – usually T cells or natural killer (NK) cells – to recognise and eliminate cancer cells. CAR-T cell therapies, in particular, have been dramatically successful in treating blood cancers such as leukaemia and lymphoma, and have transformed the treatment landscape for many patients who previously had few options.

Yet even the most advanced tools have limitations. One of the less-publicised but increasingly recognised barriers to CAR therapy is a cellular phenomenon known as trogocytosis. This process, where immune cells extract fragments of membrane and surface proteins from target cells, may appear subtle, but its consequences can be profound. By altering how engineered immune cells interact with tumour cells, trogocytosis can significantly reduce the efficacy of these therapies and even lead to unintended self-destruction among therapeutic cells.

Understanding and mitigating trogocytosis is becoming a key area of focus for researchers and clinicians alike. As the field of immunotherapy expands beyond haematological cancers into the far more complex terrain of solid tumours, resolving this challenge may be critical to realising the full potential of CAR-based interventions.

Turning point in cancer therapy

Most CAR-T therapies in clinical use involve extracting a patient’s own T cells and genetically modifying them to express a synthetic receptor – the CAR – that targets a specific antigen on cancer cells. These engineered cells are then expanded and reintroduced into the patient, where they seek out and destroy cells that express the target antigen.

The design of CARs includes an antigen-recognition domain (usually derived from an antibody fragment) and intracellular signalling modules that activate the T cell upon engagement. Over the past few years this approach has proven to be a game changer for certain blood cancers, leading to durable remissions in patients with otherwise refractory disease. In the US, seven CAR-T therapies have been approved by the US Food and Drug Administration, with thousands more being explored in various tests and trials around the world.

However, while the headlines have focused on success stories, scientists working in this area have long observed that in some patients the CAR-T cells disappear prematurely or lose their effectiveness despite a clear initial response.

By altering how engineered immune cells interact with tumour cells, trogocytosis can reduce the efficacy of these therapies

Trogocytosis is not unique to CAR cells – it is a naturally occurring process observed in various cell types – including immune cells such as T cells, B cells, dendritic cells and macrophages – where membrane fragments and associated surface proteins are transferred from one cell to another during close contact. Once considered a rare phenomenon, trogocytosis is now understood to play functional roles across a wide range of biological and physiological processes, including fertilisation, embryonic development, parasite pathogenesis and infectious diseases.

In addition, it is now recognised as a key mechanism in cell-to-cell communication, antigen presentation and immune modulation[1]Reed, J. et al. Cells 10 (2021)..

In the context of CAR-T or CAR-NK therapies, however, trogocytosis takes on a new and unintended significance. When an engineered immune cell engages a tumour cell, it may acquire surface antigens from the tumour, effectively displaying the same molecules it was designed to target. This antigen acquisition leads to several key problems.

First, the CAR cells now resemble the very tumour cells they were programmed to destroy. This confuses the immune system and, more specifically, leads other CAR cells to target and eliminate their modified counterparts, a process known as fratricide. Second, by removing key antigens from the surface of tumour cells, trogocytosis can create a population of cancer cells that no longer express the target antigen. These ‘antigen-negative’ variants are invisible to the CAR cells, free to proliferate unchecked.

The dual effects of immune cell fratricide and antigen escape profoundly undermine the long-term efficacy of CAR therapy.

A key preclinical study in 2019 by researchers at the Memorial Sloan Kettering Cancer Center, New York, demonstrated this process in action. Researchers studying anti-CD19 CAR-T cells found that T cells that engaged CD19+ tumour cells absorbed CD19 and were subsequently killed by other CD19-targeting CAR-T cells. This fratricide reduced the overall population of effector therapeutic cells and contributed to treatment failure[2]Hamieh, M. et al. Nature 568, 112–116 (2019).. Subsequent studies have extended this phenomenon to CAR-NK cells, which similarly engage in trogocytosis and suffer from reduced persistence due to self-targeting[3]Li, Y. et al. Nat. Med. 28, 2133–144 (2022).. In both cases, antigen density on tumour cells is also reduced, limiting the capacity of CAR cells to recognise and destroy them.

Cholesterol's unexpected role 

Digging deeper, researchers have started to uncover the molecular mechanisms that govern trogocytosis. One particularly interesting discovery relates to cholesterol metabolism in CAR-T cells[4]Lu, Z. et al. Cell Metab. 34, 1342–1358 e1347 (2022).. Researchers at the University of Pennsylvania found that certain signals in the tumour microenvironment induce the expression of activating transcription factor 3 (ATF3) in CAR-T cells. ATF3 suppresses the expression of CH25H, an enzyme responsible for converting cholesterol into 25-hydroxycholesterol (25HC).

Why does this matter? 25HC appears to play a protective role against trogocytosis. When CH25H is downregulated, trogocytosis is amplified, allowing tumour antigens to be more readily absorbed by the surface of CAR-T cells. However, when CH25H is induced, either genetically or pharmacologically, CAR-T cells produce more 25HC, which in turn limits trogocytosis, reduces fratricide, and enhances persistence and cytotoxicity.

This metabolic axis has opened new avenues for pharmacological intervention. By modulating cholesterol pathways, scientists can influence how CAR cells interact with tumours without altering the antigen-recognition machinery itself.

Rethinking design

In parallel with biochemical strategies, researchers are pursuing structural solutions to the trogocytosis problem. One promising approach is the development of lower-affinity CARs[5]Olson, M.L. et al. Leukemia 36, 1943–1946 (2022).. High-affinity CARs bind strongly to their target antigen, but also increase the likelihood of trogocytic transfer. Lower-affinity CARs, by contrast, still engage the antigen, but are less likely to remove it from the tumour cell surface. Early studies suggest these modified CARs retain their ability to kill tumour cells and produce key cytokines, while reducing the risk of fratricide and antigen escape.

Understanding and mitigating trogocytosis is essential for expanding the scope of CAR interventions into new cancer types

Another innovation involves the use of inhibitory CARs, particularly in NK cells[3]. These modified receptors are designed to recognise when a CAR-NK cell has acquired antigens from a tumour cell and deliver a suppressive signal instead of an activating one. This allows CAR-NK cells to differentiate between malignant cells and fellow immune cells that have inadvertently absorbed antigens, preserving the therapeutic population and minimising auto-reactivity.

Why trogocytosis matters now 

As of the end of 2025 there were more than 1,500 registered clinical trials investigating CAR-T therapies worldwide[6]Cao, L.Y. et al. Front. Immunol. 16 (2025). and at least 119 involving CAR-NK cells[7]Jørgensen, L.V. et al. Exp. Hematol. Oncol. 14, 46 (2025)., with applications ranging from haematologic malignancies to solid tumours and even infectious diseases. The enthusiasm surrounding this field is justified, but there are many challenges preventing this type of therapy from being a silver bullet.

Solid tumours, in particular, present unique immunological hurdles. Unlike blood cancers, which typically express homogeneous and accessible antigens, solid tumours often exhibit a diversity of antigens, along with physical barriers preventing infiltration by immune cells and immunosuppressive microenvironments. With such challenges for modified immune cells to overcome, it is vital to ensure trogocytosis is minimised.

Understanding and mitigating trogocytosis is essential not just for improving current therapies, but for expanding the scope of CAR interventions into new cancer types and patient populations. Failing to address this common cellular process in the design of CAR-T and CAR-NK therapies could limit what is otherwise a revolutionary therapeutic approach. It is no longer something drug design can afford to overlook and needs to be part of the conversation as we refine and improve next-generation CAR designs.

CAR-T performance can also be affected by factors such as T cell exhaustion, checkpoint inhibition, the tumour microenvironment and the physical barriers that limit T cell access to tumours. A complete understanding of these interconnected mechanisms will be essential to designing truly durable and effective therapies. Even as we harness the immune system’s power, we must remain attentive to its complexities and feedback loops.

Deborah Agbakwuru MRSB is a PhD researcher in immunology at the University of Montana focusing on T cell biology and immune regulation

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