The implications reach well beyond basic cell biology. Because red blood cells traverse the body every few seconds, they constantly swing between oxygen-rich environments in the lungs and oxygen-poor environments in working muscle, inflamed tissue, or the circulation of someone bleeding from trauma. Understanding how they cope with that oscillation could reshape approaches to high-altitude acclimatization, athletic performance, hemorrhagic shock, and even the storage of blood for transfusion. The study, led by senior author Angelo D’Alessandro, professor of biochemistry and molecular genetics at CU Anschutz, suggests that the humble red blood cell is running a sophisticated control system that operates entirely without new protein synthesis.

That constraint is what makes the finding remarkable. Nearly every other cell in the body responds to environmental stress by switching genes on or off, transcribing new messenger RNA, and manufacturing fresh proteins tailored to the challenge. Mature red blood cells, having ejected their nuclei during development, cannot do any of this. They carry only the protein complement they were born with, roughly 120 days’ worth of molecular equipment that must last their entire circulating lifespan. D’Alessandro and his colleagues found that the cells compensate by continually reorganizing the proteins they already have, shifting which molecules bind to which, and rerouting metabolic traffic through existing enzymatic machinery. In effect, protein interactions themselves become a form of rapid biological regulation, a substitute for the genetic control that other cells rely on.

At the center of this oxygen-sensitive network sits Band 3, the most abundant protein in the red blood cell membrane and a molecule long known for anchoring the cell’s structural skeleton and shuttling chloride and bicarbonate across the membrane. The new study reveals that Band 3 does far more than structural housekeeping. When hemoglobin releases oxygen and enters its deoxygenated state, its binding to Band 3 increases approximately threefold, a shift that propagates through the network and triggers cascading changes in the cell’s metabolism. The researchers also discovered a previously unknown interaction between Band 3 and an enzyme called biliverdin reductase B, or BLVRB, a connection that links events at the cell membrane to the metabolic machinery operating inside the cell.

The scale of the remodeling is striking. When oxygen levels dropped, nearly one-third of all mapped protein interactions were altered. Glucose metabolism shifted into different channels, and production of 2,3-bisphosphoglycerate, commonly abbreviated 2,3-BPG, increased. That small molecule is one of the most important regulators in human physiology, yet it is rarely a household name. 2,3-BPG wedges itself into hemoglobin and weakens the bond between hemoglobin and oxygen, allowing red blood cells to release their cargo more readily to tissues that are starved for it. In other words, when oxygen becomes scarce, the red blood cell does not simply passively carry less oxygen; it actively reprograms its own chemistry to deliver more of what remains.

This mechanism may finally explain, at the molecular level, a phenomenon physiologists have observed for decades. People who travel to or live at high altitude are known to raise the 2,3-BPG content of their red blood cells, a change that compensates for the reduced oxygen pressure in thin mountain air. The new study identifies part of the molecular machinery that coordinates that response, connecting the oxygen state of hemoglobin to the enzymatic pathway that synthesizes 2,3-BPG. To test whether the mechanism mattered in a living organism rather than only in a test tube, the researchers turned to animal models engineered to lack the oxygen-responsive N-terminal region of Band 3. The result was unambiguous: their red blood cells could no longer mount the normal metabolic response to low oxygen, and the animals showed impaired exercise capacity.

The researchers also uncovered an additional layer of regulation involving nitric oxide, a signaling molecule central to blood vessel function. In the newly mapped network, BLVRB acts as a molecular relay, accepting a nitric oxide-derived chemical signal and passing it to another enzyme that directly regulates 2,3-BPG synthesis. This relay helps redirect how the cell uses glucose when oxygen levels fall, steering metabolic flux toward the pathway that produces the oxygen-releasing molecule. Perhaps the most unexpected twist in the story is evolutionary: plants have independently evolved to use essentially the same chemical switch to generate molecules that regulate photosynthesis, redirecting carbon metabolism in response to changing gases. The same basic redox chemistry appears to have been recruited twice, in kingdoms of life separated by more than a billion years of evolution, to solve the same problem of matching metabolism to the surrounding atmosphere.

D’Alessandro notes that the parallel is more than a curiosity. In a red blood cell, the switch helps metabolism respond to changing oxygen; in a plant, it helps redirect carbon toward photosynthesis. Evolution, it seems, has repeatedly converged on the same molecular solution for adapting metabolism to the gaseous environment. For human physiology, the practical consequences could be significant. Individual variation in this oxygen-responsive network might underlie differences in how well people acclimatize to altitude, how effectively they perform endurance exercise, and how vulnerable their red blood cells are to breakdown under stress. The findings also carry implications for blood banking, where stored red blood cells endure prolonged oxygen and metabolic stress that degrades their function, and for critical care, where trauma and hemorrhagic shock deprive tissues of oxygen delivery in ways that this network may normally help buffer.

To accelerate that translational work, the team has made its detailed red blood cell protein database, called Deep Red, publicly available, giving other scientists a comprehensive map of the proteins and interactions that govern the cell’s behavior. The study brought together researchers from CU Anschutz and collaborating institutions across the United States and Canada, and its significance was highlighted by an accompanying editorial in Blood and a featured discussion on the American Society of Hematology Podcast. The work was supported by the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences. What began as an effort to catalog the proteins in the body’s most numerous cell has instead revealed a fast-acting, evolutionarily ancient control system, hidden inside a cell that was never supposed to be capable of regulation at all.

Subject of Research: The red blood cell proteome and interactome regulating hypoxic metabolic adaptation

Article Title: Scientists map the hidden protein network that helps red blood cells adapt to oxygen

Article References: Scientists map the hidden protein network that helps red blood cells adapt to oxygen. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: red blood cells, Band 3, BLVRB, 2,3-BPG, hypoxia, hemoglobin, high altitude, exercise capacity, nitric oxide, proteome, Blood journal, CU Anschutz

The therapy belongs to a class of treatments known as CAR T-cell immunotherapy. The process begins with the collection of a patient’s own T cells, the immune system’s specialized killers. In the laboratory, those cells are genetically modified so that they carry engineered receptors capable of recognizing and binding to specific molecules on the surface of cancer cells. Once reprogrammed, the cells are expanded into large numbers and returned to the patient, where they circulate, seek out their targets and attack. The technique has already produced striking results in certain blood cancers, including leukemia and lymphoma, where engineered immune cells have driven durable remissions in patients who had exhausted every other option.

Translating that success to solid tumors such as colorectal cancer has proved far more difficult. Solid tumors are physically dense, immunologically hostile environments that engineered cells struggle to infiltrate and survive in. They deploy molecular defenses that suppress or redirect immune attacks, and they present a fundamental targeting problem: researchers must find a molecule that is abundant on cancer cells but scarce on healthy tissue, so that the therapy attacks the tumor without destroying vital organs. That targeting challenge has been one of the central obstacles holding back CAR T-cell therapy for the many cancers that form solid masses rather than circulating freely in the blood.

The CU Anschutz team believes it has found a way around that obstacle by aiming at two targets at once. The first is B7-H3, a protein found on the surface of most colorectal tumors and, importantly, on a wide range of other cancers as well. Researchers at several institutions have been investigating B7-H3 as a potential cancer target precisely because of its broad presence across tumor types. The second target is IL-8, a signaling protein that helps promote tumor growth, inflammation and the spread of cancer through the body. By simultaneously targeting B7-H3 and the IL-8 pathway, the engineered cells are designed to strike both the tumor itself and one of the biological systems it uses to grow and evade immune destruction. The researchers hope that this two-pronged strategy will give the engineered cells a better chance of overcoming the defenses that have limited earlier attempts to treat solid tumors with CAR T-cell therapy.

The dual-target design also reflects a deliberate strategic choice about which patients the therapy could eventually serve. Michael Verneris, MD, professor of pediatric oncology at CU Anschutz and program co-leader of Tumor-Host Interactions at the CU Anschutz Cancer Center, said the team wanted to move away from highly narrow approaches. “This is a very different way of thinking about how we treat cancer,” Verneris said. “We wanted to find targets that are present across many different cancers rather than developing a therapy that would only apply to a small number of patients.” If the trial demonstrates that the approach is safe and effective, the researchers say it could eventually be tested against other cancers in which these pathways play a role, including some breast, lung and ovarian cancers.

Christopher Lieu, MD, professor of medical oncology at CU Anschutz and associate director of clinical research at the CU Anschutz Cancer Center, is leading the trial. He framed the therapy as a potential alternative to the blunt instruments of conventional treatment. “Chemotherapy extends survival and helps cure people,” Lieu said. “At the same time, it’s like dropping an unguided bomb on a disease. Maybe you hit your target, but you are going to do a lot of collateral damage.” He is hoping the therapy, which has proven effective in animal models, will produce far longer-lasting results than current options typically deliver. “Immunotherapy gives us the opportunity to direct the immune system toward the cancer and potentially produce a much more durable response,” he said. The goal, he added, is not measured in months but in years.

The urgency behind the trial is underscored by troubling epidemiological trends. Colorectal cancer is increasingly affecting younger adults, with rates among people under 45 rising substantially over the past several decades while researchers continue to investigate the reasons behind the shift. For patients whose disease advances despite standard therapies, options narrow rapidly. Currently, only a small percentage of patients with colorectal and other gastrointestinal cancers qualify for certain forms of immunotherapy, because those treatments depend on specific tumor biomarkers that many patients do not have. Because B7-H3 is present in a much larger proportion of colorectal cancers, the researchers hope their approach could ultimately be applicable to a far broader patient population. “Given the number of patients we are seeing, we need new approaches,” Lieu said. But he and his colleagues are careful to note that the first step is determining whether the therapy is safe in people and whether it can effectively attack cancer in the human body, as it has in animal models.

The path from concept to clinical trial also highlights the structural advantages of the CU Anschutz campus, which brings together the university’s health professional schools, Children’s Hospital Colorado, UCHealth University of Colorado Hospital and the Gates Biomanufacturing Facility within easy walking distance of one another. The experimental cells for the trial will be manufactured at the Gates Biomanufacturing Facility, meaning the entire pipeline, from basic research to cell production to patient treatment, exists on a single campus. “The whole spectrum is right here,” Verneris said. “If we didn’t have the Gates Institute, we wouldn’t be able to make our own cells. This could have remained an interesting idea. Instead, it has become a clinical trial that could have a real impact on patients.” Philanthropic support has been essential to reaching this point, Verneris noted, because trials of this kind are expensive and private donations made it possible to move the therapy from the laboratory into patients. “We are incredibly grateful to the donors who have helped make this possible,” he said.

For the patients who enroll, the trial represents something that advanced colorectal cancer currently offers in short supply: a chance at a treatment designed to last. If the engineered cells can safely navigate the hostile terrain of solid tumors and dismantle the pathways that colorectal cancers use to grow and spread, the trial could open a new front against one of the most common and increasingly prevalent cancers, and potentially against several others beyond it. The FDA’s clearance now allows that hypothesis to be tested in the place it matters most, in the bodies of the patients the therapy was designed for.

Subject of Research: A first-in-human clinical trial of dual-target CAR T-cell immunotherapy for advanced colorectal cancer

Article Title: FDA clears CU Anschutz clinical trial using engineered immune cells to fight colorectal cancer

Article References: FDA clears CU Anschutz clinical trial using engineered immune cells to fight colorectal cancer. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: CAR T-cell therapy, colorectal cancer, FDA clearance, clinical trial, immunotherapy, B7-H3, IL-8, solid tumors, CU Anschutz, pediatric cancer, engineered immune cells, Gates Biomanufacturing Facility