Biophysical immunoengineering: from insight to clinical application

The field of immunoengineering is newly emerging based on key developments in three distinct fields. In cellular immunology, super-resolution optical microscopy and molecular sensors are revealing biophysical signalling. In biophysics and bioengineering, an increasing body of research demonstrates the critical impact of physical phenomena – mechanical forces and spatial nanostructure – on cell behaviour across tissues. Finally, and perhaps most importantly, new-generation immunotherapies are revolutionizing cancer medicine. This Discussion offers a chance to reflect on these developments, and to consider future directions for the field, from both fundamental and clinical perspectives.

Dr Iain E Dunlop

Imperial College London, UK

Dr Iain E Dunlop

Imperial College London, UK

Dr Iain Dunlop is Associate Professor in Biomaterials and Cell Engineering, at Dept. Materials, Faculty of Engineering, Imperial College London. His MSci degree was in Natural Sciences (Physics) from the University of Cambridge, followed by doctoral (DPhil) work in soft matter at Dept. Chemistry, University of Oxford. He then moved into biophysics, as an Alexander von Humboldt Fellow, Dept. New Materials and Biosystems, Max Planck Institute for Metals Research, Stuttgart. His laboratory develops advanced biofunctional nanoparticles and complex gels, with a focus on opening up new biologically complex applications. His laboratory has played a pioneering role in immunoengineering: in early work exploiting nanolithography to reveal fundamental nanospatial constraints on activation in T cells and Natural Killer cells. His recent research has discovered new biophysical design rules for immunomodulatory nanomaterials. Beyond immunoengineering, his laboratory works also on biophysical drivers of disease, for example photoresponsive gels to reveal mechanobiological effects in respiratory disease organoid models.

The immunological synapses (IS) is the specialized contact between a T cell and antigen presenting cell that serves effector function for helper and cytotoxic T cells. Dynamic imaging of the immunological synapse provided a framework how T cells could measure and respond to physical forces. A key feature of the IS is the transport of TCR microclusters to the centre, where signalling is terminated. We discovered using correlative light and electron microscopy that TCR were ectocytosed in the centre of the synapse. These vesicles also serve as an antigen specific carrier for CD40-ligand, a critical signal delivered by helper T cells1. We next adapted our technology to investigate how CD8 cytotoxic T cells (CTL) and NK cells use nanoscale protein “bombs” with a core of cytotoxic perforin and granzymes and a shell of thrombospondin-1 (TSP-1) that are secreted into the synaptic cleft to kill target cells 2. We have referred to these “bombs” as supramolecular attack particles (SMAPs).

While the radially symmetric synapse has clear benefits for effector function, the control of proliferation is less clear. Work led by Dr Alexander Leithner has recently developed a new method to selectively control the lateral mobility of one component in a synthetic bilayer at a time, which has revealed new requirements for costimulatory signalling by the ICAM1 integrin ligand based on mechanical feedback. Physical resistance to transport greatly enhances T cell responses. T cell may sense not only the presence of adhesion ligands, but the state of the target cell and its environment through physical forces on the pN to nN scale.

Professor Michael Dustin FRS

University of Oxford, UK

Professor Michael Dustin FRS

University of Oxford, UK

Professor Dustin FRS has a BA from Boston University and a PhD from Harvard University. His interests are cell biology and immunology. His lab at Washington University led pioneering work on two-dimensional affinity in cell adhesion and the immunological synapse. At the Skirball Institute of NYU School of medicine he explored in vivo dynamics of the immune response using two-photon laser scanning microscopy and developed a new program in mechanobiology of the immunological synapse. At the Kennedy Institute of Rheumatology of the University of Oxford he has explored the nanoscale organization of the immunological synapse leading to a basic description of its supramolecular assemblies. Surprising findings included supramolecular attack particles that mediate cytotoxicity. He holds a Presidential Early Career Award in Science and Engineering, is a member of European Molecular Biology Organization and National Academy of Sciences, and is a Fellow of the Royal Society.

B cells, the antibody-producing cells of the adaptive immune system, detect and discriminate antigens through mechanical interactions between their surface B cell receptors (BCRs) and antigens displayed on antigen-presenting cells (APCs). These interactions take place within immune synapses—specialised contact zones between B cells and APCs—where B cells apply mechanical forces to test antigen binding strength. This mechanosensing process underlies B cells’ ability to select high-affinity targets and mount effective antibody responses. To uncover the physical principles governing this behaviour, we combine high-resolution fluorescence microscopy with DNA-based molecular tension sensors and supported lipid bilayers. This integrated approach allows us to visualise BCR signalling dynamics while quantitatively measuring the piconewton-scale forces that B cells exert on individual antigens. By precisely tuning antigen mobility and spatial organisation, we reveal how biophysical properties of antigen presentation influence the sensitivity and specificity of B cell activation. These findings provide a quantitative, molecular-level view of how force and physical context regulate immune recognition at cell-cell interfaces.

Dr Katelyn Spillane

Imperial College London, UK

Dr Katelyn Spillane

Imperial College London, UK

Katelyn Spillane is a biophysicist interested in how immune responses are shaped by the physical environment. Her laboratory focuses on B cells, combining quantitative imaging, biophysical measurements, and computational analysis to understand how they recognise and discriminate antigens to generate protective antibodies. She holds a B.S. in Chemistry and B.A. in Music from the University of Massachusetts Amherst and a Ph.D. in Chemistry from the University of California Berkeley. She completed postdoctoral research in physical chemistry at the University of Oxford and in immune cell biology at the MRC National Institute for Medical Research (later the Francis Crick Institute). Katelyn established her independent research group in 2018 in the Department of Physics at King’s College London and moved to the Department of Life Sciences at Imperial College London in 2024.

Cytotoxic T lymphocytes (CTLs) of the immune system provide a vital defence against pathogens and cancer. There is increasing interest in understanding how these cells work as recent advances in immunotherapies have successfully harnessed the killing potential of these cells to combat cancers. How best to optimize these treatments and regulate killing is the subject of intense research. Much research has focused on modifying the receptors that recognize targets at the cell surface with the idea of improving signaling and clinical efficacy. T cell receptor (TCR) signaling triggers a remarkable series of highly co-ordinated events within CTLs including changes in membrane composition and selective shedding of activated TCRs during signaling, together with a dramatic polarization of both the secretory organelles as well as the nucleus. The nucleus contorts as it moves within the cell with the nuclear membrane puckering to cluster at the immune synapse. Nuclear polarization is required for translocation of key transcription factors NFAT and NFkB that give rise to an early transcriptional burst leading to synthesis and polarized delivery of cytokines and chemokines required for CTL infiltration into tumor spheroids. Teasing apart the molecular mechanisms controlling these pathways provides new possibilities for immunoengineering and clinical applications.

Reference:

Nuclear polarization to the immune synapse facilitates an early transcriptional burst.
Asano Y, Ma CY, Limback-Stokin M, Rochussen AM, Stinchcombe JC and Gillian M Griffiths. Science Immunology (2025) eadt5909. 

Professor Gillian Griffiths FMedSci FRS

University of Cambridge, UK

Professor Gillian Griffiths FMedSci FRS

University of Cambridge, UK

Professor Gillian Griffiths FMedSci FRS obtained her PhD at the MRC Laboratory of Molecular Biology with Cesar Milstein. After a post-doctoral fellowship at Stanford University, she started her own research laboratory at the Basel Institute for Immunology in Switzerland in 1990. She subsequently held posts at University College London, the Dunn School of Pathology, Oxford (1997-2007) before moving to the Cambridge Institute for Medical Research where she was Director 2102-2017. She was elected as a Fellow of the Academy of Medical Sciences (2005); EMBO (2006), and the Royal Society (2013). She was awarded the Royal Society Buchanan medal (2019) in recognition of her ground-breaking research establishing the fundamental cell biological mechanisms that drive CTL killing, laying the foundations for the development of targeted cancer immunotherapy. Professor Griffiths is currently the Anthony N Brady Professor and Chair of Cell Biology at Yale University School of Medicine.

The immune system is a compelling platform for precise, potent, and persistent therapies targeting an ever-increasing range of diseases. T cells are now deployed as “living drugs” against cancers and a growing list of diseases. Across these approaches, the ability of T cells to sense the mechanical response of their environment offers new routes for directing the immune response.

In the theme of this meeting, we present both new insights into the mechanisms through which T cells carry out mechanosensing and strategies for addressing the variability of this behavior between individuals. In particular, this talk discusses how machine learning can advance clinical applications of T cell mechanosensing. Most strikingly, this includes prediction of long-term response of T cells to biomaterials from short-term assays of high-level cellular function. These approaches also delineate interactions between subsets of T cells, demonstrating that population-level mechanosensing requires collaboration between cells with different functions. These studies have predominantly focused on cells interacting with locally planar substrates, a mainstay of biomaterials development. However, we also demonstrate that T cells can sense the three-dimensional, micrometer-scale structure and rigidity of materials. These interactions are mediated by the extension of cellular processes into material structure, offering new avenues for engineering T cell function.

Professor Lance Kam

Columbia University, USA

Professor Lance Kam

Columbia University, USA

Known for innovative advances at intersections between fields, Lance Kam is a Professor of Biomedical Engineering and Medical Sciences at Columbia University. His team studies how cells interact with complex biomolecular and mechanical cues of their environments, building new strategies for directing cell function. Most recently, this work has focused on mechanobiology of T cells, from identifying mechanisms by which these cells carry out sensing to developing practical tools for immunotherapy. Dr Kam earned his PhD from Rensselaer Polytechnic Institute and completed postdoctoral training at Stanford University before starting his independent career at Columbia University. He is an AIMBE Fellow, and Chair of Graduate Studies for Columbia Biomedical Engineering.

Our immune system interacts with many diseases in a multidimensional manner involving substantial biological, chemical, and physical exchanges. Manipulating the disease-immunity interactions may afford novel immunotherapies to better treat diseases such as cancer, an emerging field termed ‘immunoengineering’. My lab aims to develop novel strategies to engineer the multidimensional immunity-disease interactions to create safe and effective therapies against cancer. We leverage the power of metabolic and cellular bioengineering, synthetic chemistry and material engineering, and mechanical engineering to achieve controllable modulation of immune responses. In this talk, I will first discuss our discovery of a new type of immune checkpoint with mechanical basis that is distinct from most known immune checkpoints of biochemical traits. We further developed novel interventions to overcome the mechanical immune checkpoint for enhanced cancer immunotherapy. Next, I will talk about our recent discovery of IL-10 and IL-4, type 2 immune function-related cytokines, as metabolic reprogramming agents that reinvigorate the terminally exhausted CD8⁺ tumor infiltrating lymphocytes. This strategy has been extended to developing metabolically armored CAR-T cells with IL-10 secretion to counter exhaustion-associated dysfunction in the tumor microenvironment for enhanced anticancer immunity. This new CAR-T cell therapy, i.e. IL-10-secreting CAR-T, has shown promise in several on-going IIT clinical trials (NCT06393335, NCT05715606, NCT05747157, NCT06120166, NCT06277011) in the treatment of refractory/relapsed CD19⁺ B cell leukemia and lymphoma, and lupus.

Professor Li Tang

Institute of Bioengineering, EPFL, Switzerland

Professor Li Tang

Institute of Bioengineering, EPFL, Switzerland

Li Tang is an Associate Professor at EPFL’s Institute of Bioengineering and Materials Science, where he also serves as Vice Dean for Innovation at the School of Life Sciences and is co‑founder & Chair of Leman Biotech. He earned his BS in Chemistry from Peking University (2007) and his PhD in Materials Science and Engineering from the University of Illinois at Urbana‑Champaign (2012). He completed his postdoctoral training as a CRI Irvington Fellow in Prof. Darrell Irvine’s lab at MIT.

His research focuses on multidimensional immunoengineering to advance cancer immunotherapy. Prof. Tang has received many prestigious awards, including the ERC Starting Grant (2018), the Biomaterials Award for Young Investigators (2024), the Leenaards Prize (2025), Friedrich Miescher Award (2025), Highly Cited Researcher Award (2025), and Lem Prize (2025), and was named to MIT Technology Review’s “Top 35 Innovators Under 35” in China (2020).

Engineering advanced microenvironments that recapitulate key features of healthy and malignant lymphoid tissues offers new opportunities to improve both cellular immunotherapy manufacturing and disease modelling. We have developed a family of PEG–heparin biohybrid hydrogels designed to mimic essential biochemical, mechanical, and architectural cues of the extracellular matrix (ECM) of healthy lymph nodes. By tuning stiffness, pore interconnectivity, and biomolecule loading, we identified hydrogel conditions that markedly enhance the expansion and activation of primary human T cells. In particular, hydrogels featuring 120 μm interconnected pores and intermediate stiffness of 3 kPa promoted a 50% increase in CAR expression and doubled the replication index relative to conventional suspension cultures. Building on these insights, we further demonstrated that these lymph-node-inspired matrices can be manufactured at scale using 3D printing, enabling improved T cell infiltration and more efficient nutrient and gas exchange—key requirements for clinically relevant cellular manufacturing processes. Finally, we are also engineering patient-derived lymphoma tumoroids to recreate the complex immune tumour microenvironment of this disease using our lymph node-inspired artificial ECM. In this case, modifications have been introduced to mimic malignant lymph nodes. Together, these platforms enable a deeper understanding of how engineered microenvironments regulate immune cell behaviour and demonstrate their potential to both enhance CAR T-cell manufacturing and provide physiologically meaningful systems for personalized therapy testing.

Dr Judith Guasch

Materials Science Institute of Barcelona, Spain

Dr Judith Guasch

Materials Science Institute of Barcelona, Spain

Dr Judith Guasch is a Tenured Researcher at the Institute of Materials Science of Barcelona – Spanish National Research Council (ICMAB-CSIC), where she leads the Dynamic Biomimetics for Cancer Immunotherapy group. Her research focuses on engineering biomimetic materials to advance personalized medicine, with particular emphasis on cellular therapies and in vitro preclinical models. She has co-authored more than 40 publications and three patent applications. Since joining ICMAB-CSIC in 2016, she has secured over €2.6 million in competitive funding and maintains active collaborations with several clinical and research institutions across Europe, including the Max Planck Institute for Medical Research (Germany), where she is also a guest scientist.