Immunology has never lacked biological complexity.
The immune system contains an extraordinary diversity of receptors: T-cell receptors, B-cell receptors, Fc receptors and entire families of chemokine receptors. Each helps an immune cell sense a different signal, recognise a different threat or respond to a different environment.
Intriguingly, that diversity far surpasses what exists downstream. The immune system fields an enormous array of surface receptors, yet the signal transduction components sitting just beneath them are far fewer. Signals from these receptors repeatedly converge on a relatively small number of pathways: MAPK, RAS, NFAT, NF-κB, ERK, p38 and others, rather the enormous biological diversity mediated by cell surface receptors seems to be driven by highly complex networks that exist through combinatorial wiring of these nodes. By the early 2010s, many of the most obvious druggable nodes within this canonical signalling architecture had already been pursued. JAK kinases were spoken for. NFAT was spoken for. The receptors kept multiplying, but the pathways did not.
This raised a basic question for immunologists and drug developers. Although there were only a few pathways available for drug discovery, many of the targets that had been most extensively pursued within these pathways were still not enough to meet the need in immune diseases. So, where should the next generation of targets and therapies come from?
Across three decades in immunology, Hozefa Bandukwala has repeatedly encountered that question at different levels of biology. His work has moved from identifying immune-cell populations through surface markers, to studying the molecular programs that define their identity, to exploring the metabolic machinery that enables their function. The progression reflects a broader shift in the field itself: from asking what sits on the surface of an immune cell to understanding what creates and sustains the state within it.
Bandukwala has spent the last fifteen years shaping drug discovery across Pfizer, Third Rock Ventures and Flagship Pioneering. His academic training and translational research often placed him close to important changes in how scientists understood the immune system. During his undergraduate years in the 1990s, Bandukwala encountered an article explaining one of the early ideas behind antibody-drug conjugates: use an antibody to carry a therapeutic payload directly to a tumour cell, with the precision of a guided missile. It was, he says, "such a fascinating concept," unlike anything he had encountered before.
Immunology appeared unusual because it was not only a field of biology. It could also become the modality through which disease was treated. Antibodies could be both objects of scientific investigation and medicines in their own right. The same was later true of cell therapies such as CAR-T. "This is one field where the field itself is both biology and modality," he says. "Very few other fields open themselves up like that."
Immunology offered a place to investigate both the mechanism and the intervention. It also gave him a view of how deeply immune biology reaches into medicine. Nearly everyone takes a steroid or an allergy medication at some point in life, he points out, and "all of those are immune mediated processes."
But the way scientists defined immune cells at the time was still largely phenotypic. During his PhD, Bandukwala worked within the classical framework of cellular immunology. Researchers isolated specific immune-cell populations, transferred them between animal models and studied the resulting effects. Cells were commonly defined using markers such as CD4, CD8 and CD25. These markers were experimentally powerful, allowing scientists to separate populations, track them and associate them with particular immune functions. Yet they also described cells primarily from the outside. Bandukwala began to feel that his understanding of the immune system was "literally stuck at the surface level." The field could identify a population by the markers it expressed, and could observe what that population did. But surface identity alone did not fully explain the internal regulatory programs that made the cell behave that way.
A conversation with his postdoctoral advisor, Anjana Rao, pushed Bandukwala to reconsider what cellular identity meant. Rao challenged the idea that immune cells were inherently exceptional. What looked like distinct immune cell types, she argued, were better understood as a continuum of transition states. Cell types could be thought of as local minima on an energy landscape, each stable enough to persist, but not so stable that a cell identity could not be pushed from one state to another. The right intervention or stimulus, applied with enough force, could overcome the activation barrier separating them. She pointed to Shinya Yamanaka's work on induced pluripotent stem cells, which demonstrated that cellular identity could be reprogrammed using only 4 transcription factors.
For Bandukwala, the implication was immediate. If a small set of transcription factors could rewrite what a cell was, then surface markers could not be treated as the final definition of identity. The phenotype visible on the outside was being generated and maintained by molecular programs operating within the cell. Understanding immune behaviour therefore required looking beyond CD markers and receptor expression, toward the transcription factors, signalling networks and nuclear processes that governed cellular state. This marked his movement from cellular immunology into molecular immunology.
The shift coincided with a broader inflection point in biology. The completion of the human genome sequence created a foundational map of genes and proteins and enabled researchers to ask biological questions at a scale that conventional candidate-by-candidate experimentation could not support. Bandukwala is emphatic that this is under-appreciated by those who argue little came of the genome project: "They could not be more wrong," he says.
He watched what it made possible at close range. In Rao's laboratory, a genome-wide RNA interference screen helped identify ORAI1, the long-elusive calcium channel that had resisted conventional biochemical discovery for more than two decades. The finding gained further biological credibility when patients carrying mutations in the gene were found to present with immunodeficiency. The sequence of evidence mattered: a system-wide experimental screen identified a candidate, and human genetics then connected that candidate to immune dysfunction. It illustrated how the emerging tools of systems biology could reveal mechanisms that traditional approaches had been unable to resolve.
Bandukwala describes his own training as a passage through three epochs (cellular, molecular and systems immunology), each of which took the field one level deeper: from identifying immune-cell populations, to examining the molecular programs within those populations, to studying immune function through interconnected systems. The field was no longer only asking which cells were present or which receptors they expressed. It was beginning to ask which internal programs produced a particular immune state, and which dependencies were required to sustain it.
Around 2013, he attended a seminar with a deliberately provocative title: "Is the Era of the Small Molecule Over?" The question reflected a real strategic tension. Highly effective monoclonal antibodies, including IL-17 inhibitors in psoriasis, were demonstrating levels of efficacy that changed expectations for immune-mediated disease. The rise of antibody therapeutics therefore raised more than a modality question. It challenged how companies built around small-molecule discovery should think about the future of immunology.
Sitting in that seminar, Bandukwala returned to a bottleneck that had been developing across the field. The immune system contained a large and growing number of receptors, yet their signals repeatedly entered the same limited collection of downstream pathways. "If you look at the signal transduction pathways," he says, "it comes down to the same usual suspects." The most tractable nodes in those pathways had already attracted heavy drug-development attention, and identifying yet another receptor rarely created a genuinely new therapeutic mechanism, because it relied on the same familiar signalling architecture. This was further complicated by the redundancy in the immune systems where simply blocking a cell surface receptor failed to translate to a therapeutic benefit. Essentially, he realized that a large proportion of medicines were stuck at the cell surface.
But an activated immune cell was not defined only by the receptors it expressed. Activation transformed the cell's entire functional state. A primed B cell could produce, by Bandukwala's description, a hundred times its body weight in antibodies per day. An activated T cell might divide every 4 hours. Immune cells migrated through narrow capillaries, reorganised their cytoskeletons and rapidly expanded the production of proteins, membranes and nucleotides. These behaviours imposed enormous energetic and biosynthetic demands. The question was no longer only which signal instructed the cell to activate. It was also what machinery allowed that activated state to exist.
That machinery was metabolism.
Bandukwala's proposal was to move beneath receptor signalling and investigate the metabolic processes powering immune-cell behaviour.
"It was just like the theme of the movie Return of the Jedi," he says. "Take out the power reactor, you take out the Death Star."
The analogy carried a deeper scientific hypothesis. Rather than inhibiting each external signal or downstream pathway independently, it might be possible to identify metabolic dependencies shared by the functional programs required for pathological immune activation. This did not mean that metabolism was merely an energy supply operating identically in every cell. The therapeutic opportunity lay in the possibility that a cell's metabolic requirements changed with its state. A resting immune cell and a rapidly proliferating, cytokine-producing or antibody-secreting immune cell might use many of the same core pathways, but the degree to which they depended on particular enzymes, substrates or biosynthetic processes could differ substantially. The relevant target-discovery question therefore became: which metabolic processes become disproportionately important when an immune cell enters a disease-relevant state?
For Bandukwala, this expanded the potential search space. Instead of repeatedly working across a limited group of familiar signalling proteins, immunometabolism provided access to thousands of enzymes. Many had known crystal structures, existing tool compounds and biochemistry that could be reproduced in experimentally tractable assays. For chemists, this represented a large and comparatively underexplored landscape; for immunologists, it offered a new way to connect cellular function with therapeutic vulnerability. But it also raised an immediate translational problem.
Metabolic pathways are not exclusive to immune cells. They operate throughout the body and support the function of tissues with significant and continuous energetic demands. Some scientists therefore worried that inhibiting metabolic enzymes would produce unacceptable toxicity, including effects on cardiac tissue.
He made the argument from clinical precedent. Before many patients with rheumatoid arthritis receive a biologic, they are commonly treated with methotrexate, a dihydrofolate reductase inhibitor that acts on an enzyme used across the body rather than one exclusive to immune cells. Corticosteroids act through steroid hormone receptors and reshape metabolic and transcriptional programs. Leflunomide interferes with nucleotide synthesis. His conclusion was blunter than any single example: "A significant proportion of immune therapeutics were essentially low dose chemotherapy." Some of the field's most established therapies were therefore already modifying metabolic or biosynthetic processes. The principle was not new. The opportunity was to make it more precise.
The argument reframed a therapeutic paradigm. A therapeutically useful target did not necessarily have to be expressed only in a diseased immune cell. It had to create a sufficiently different dependency between the pathological and healthy states to support a viable therapeutic window. The discovery challenge was therefore not simply to identify metabolic enzymes involved in immune activation. It was to find the nodes at which disease-relevant immune function was more vulnerable than essential normal physiology.
Immuno-metabolism did more than add another target class to immunology. It changed the starting question. A receptor-led approach often begins by identifying a cell-surface molecule associated with a disease, tracing its downstream pathway and asking whether one of the resulting nodes can be modulated. A cell-state-led approach begins elsewhere: what functional state has the immune cell entered? Which transcriptional, signalling, metabolic and biosynthetic programs define that state? Which of those programs are necessary rather than merely associated with it? And where does the pathological state create a dependency that could be therapeutically exploited?
The distinction matters because immune-mediated diseases are heterogeneous. Patients classified under the same diagnosis may not share the same dominant immune-cell populations, molecular programs or mechanisms of disease, and a target that is central in one biological context may be secondary in another, an explanation the field has increasingly converged on for why response rates plateau. Bandukwala has his own shorthand for that plateau. He calls it "the rule of 30": the tendency of many immunology drugs to produce meaningful benefit in only a subset of patients, often approximately 30%. Breaking that efficacy ceiling, in his view, will require more than additional targets chosen through the same frameworks. It may require deeper resolution of disease biology, more precise definitions of immune-cell state, and better connections between mechanism, patient context and therapeutic modality.
Bandukwala also argues that the field's attention remains concentrated on a relatively small number of immune-mediated diseases, perhaps 5-10, despite the existence of more than a hundred distinct conditions. Expanding the target landscape must therefore mean more than finding additional mechanisms in already crowded indications; it must also make it possible to investigate diseases that have received less scientific and commercial attention.
The choice of modality will remain important. Advanced biological therapies can achieve remarkable efficacy, but access, cost and manufacturing complexity influence whether those therapies reach patients at scale. Small molecules remain relevant because they can often be produced more cheaply and distributed more broadly than antibodies or complex cell-based therapies. Bandukwala considers this particularly important in countries such as India, which already manufactures much of the world's medicine: "Why do we have to force ourselves to make antibodies all the time?" The timing of intervention may also change how targets are evaluated. Immune activation is self-amplifying by evolutionary design, and once inflammatory feedback loops become established, reversing the disease state can become increasingly difficult. "We have to stop treating disease and start preventing disease," he says. "Once disease starts, it's already too late." Targets that permit earlier intervention, before those loops are fully engaged, may therefore offer a different route to therapeutic impact than targets used only after disease biology has become entrenched.
Bandukwala is careful not to present immuno-metabolism as a permanently ascendant field. Scientific areas move in waves, he says. Some receive intense attention and then recede as technologies, capital and organisational priorities shift. The visibility of immuno-metabolism may be lower today than at its peak, but that does not eliminate the underlying biological logic. Immune-cell function still requires energy, substrates and biosynthetic machinery. Disease-relevant states still create dependencies. The challenge is to identify which dependencies are causal, selective and therapeutically tractable.
That distinction captures a principle that has followed Bandukwala across biologics, small molecules, gene therapy and cell therapy.
"If you want to do science, do something different," he says. "If you want to make medicines, you have to follow the KISS philosophy. Keep It Short and Simple."
The biology required to identify a meaningful target may be complex. It may demand functional genomics, human genetics, systems-level measurements and a detailed understanding of cell state. But a medicine still requires a hypothesis that can be clearly explained, experimentally tested and translated into a product. The more complicated the therapeutic proposition becomes, Bandukwala believes, the less likely it is to survive the path from scientific insight to clinical development. It is a deceptively simple standard for a scientific career that has repeatedly moved beneath the prevailing level of explanation: from surface markers, to molecular programs, to systems biology and metabolic dependencies. The broader lesson for target discovery is not that every answer lies in metabolism. It is that when an established map begins to produce the same targets repeatedly, the field may need to reconsider the level of biology at which it is searching.
The next target may not be another receptor on the surface. It may be the dependency that makes a disease-relevant cellular state possible in the first place.
Written by Arushi Batra, PhD, based on a conversation with Dr. Hozefa Bandukwala as part of Elucidata's Target Discovery: Lessons from the Field series, spotlighting voices and experiences from drug and target discovery.
.svg)
%201.svg){kind=icon}
.svg){kind=icon}
