Scientists at the University of Southern California (USC) have discovered a groundbreaking method to produce a potentially renewable and scalable supply of cancer-fighting immune cells, marking a significant step forward in the evolution of cellular immunotherapy. By working with immature progenitor cells that hold the capacity to develop into powerful immune defenders, researchers have engineered a system capable of generating large quantities of specialized cells. These engineered cells are designed to recognize malignant tumors, home in on diseased tissue, and actively stimulate the body’s natural defense systems.
The breakthrough, detailed in a prominent study published in the scientific journal Cell, addresses and potentially overcomes some of the most stubborn hurdles facing modern cancer immunotherapy. Historically, manufacturing a sufficient volume of therapeutic immune cells outside the human body has presented immense logistical and technical challenges. Furthermore, once introduced into a patient, these cells often struggle to survive, multiply, or maintain their therapeutic activity. In preclinical experiments involving mice, however, the newly engineered cells successfully established themselves within the bone marrow, continuously produced fresh waves of active immune cells, and notably slowed the progression of both aggressive blood cancers and complex solid tumors.
Led by a team of researchers at USC Stem Cell, the investigation focused specifically on granulocyte-monocyte progenitors, commonly known as GMPs. These immature cells normally serve as precursors in the blood-forming system, eventually maturing into macrophages and other essential immune cells that shield the body against harmful infections and orchestrate broader immune responses. Through careful experimentation, the research team discovered that GMPs could be extensively cultivated and expanded in a laboratory environment while successfully retaining their intrinsic ability to develop into fully functioning immune cells. Moreover, these progenitor cells could be effectively modified using genetic engineering techniques to recognize specific tumor-associated markers, thereby sharpening their targeting capabilities and boosting overall immune surveillance.
"The study establishes a scalable and engineerable GMP platform for cellular immunotherapy and introduces concepts that we believe could have broad implications for both cancer immunotherapy and stem cell biology," said the paper’s corresponding author, Qi-Long Ying, MD, PhD, a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
Scientists Discover a Surprising Ability in Immune Cell Precursors
Beyond its immediate implications for oncology, the discovery challenges long-held scientific dogmas regarding how blood and immune cells develop and differentiate within the human body. Within regenerative medicine, stem cells have long been celebrated for their remarkable capacity for self-renewal—the ability to divide repeatedly while meticulously preserving their original, uncommitted properties. In the complex ecosystem of the blood-forming system, this self-renewing power has traditionally been attributed almost exclusively to hematopoietic stem cells, which sit at the top of the developmental hierarchy and possess the unique capacity to generate every major type of blood and immune cell.
Progenitor cells, by contrast, occupy a lower tier in the developmental journey. Having progressed further along a specific lineage, they are generally understood to be committed to producing a much narrower, more limited range of mature cell types. Consequently, conventional immunological theory dictated that progenitor cells possessed a severely restricted capacity for long-term self-renewal and expansion.
The USC researchers fundamentally challenged this paradigm by demonstrating that GMPs can retain the capacity for extensive self-renewal when maintained under strictly controlled laboratory conditions. Instead of rapidly maturing and losing their proliferative potential as expected, the progenitor populations continued to multiply exponentially while steadfastly preserving their distinct cellular identity and their underlying ability to generate functional immune cells upon command.
"The prevailing view has been that long-term self-renewal in the blood system is primarily a property of the hematopoietic stem cells that can generate any type of blood or immune cell," Dr. Ying explained. "We found that, under the right conditions, GMPs can also self-renew, dividing extensively while keeping their identity and ability to produce functional immune cells. That gives us a scalable starting point for engineering cell therapies for cancer, infectious disease and potentially many other conditions."
This revelation could prove particularly vital for the development of next-generation treatments that demand massive, reliable supplies of genetically modified immune cells to achieve therapeutic efficacy in human patients.
Why Macrophages Could Be Powerful Weapons Against Cancer
To understand the strategic value of targeting GMPs, researchers looked closely at macrophages, which rank among the most versatile and potent defenders within the human immune system. Derived from Greek roots meaning "big eaters," macrophages earn their moniker through their extraordinary ability to physically surround, engulf, and digest bacteria, cellular debris, and other foreign or unwanted material. Beyond their direct phagocytic duties, they play an essential role in coordinating the broader immune response by releasing chemical signals that recruit and direct the behavior of neighboring immune cells. Certain specialized macrophages are also capable of infiltrating the dense microenvironments of tumors to attack malignant cells directly, making them exceptionally attractive candidates for cancer immunotherapy.
This attribute is particularly valuable when considering solid tumors—cancers that form distinct masses in vital organs and tissues, such as the lungs, breast, or colon. While existing cell-based therapies, such as chimeric antigen receptor (CAR) T-cell therapies, have achieved remarkable, historic successes in treating certain blood-based malignancies, treating solid tumors has historically proven significantly more difficult due to the immunosuppressive barriers erected by the tumor microenvironment.
Macrophages offer an alternative therapeutic avenue because they naturally possess the ability to migrate into deep tissue spaces and physically penetrate solid tumors. However, translating this natural biology into practical, scalable clinical treatments has presented researchers with a series of formidable hurdles.
Once macrophages reach full maturity inside the body, they become notoriously difficult to multiply in large quantities outside of it. They are also challenging to modify using genetic engineering tools, and their delicate cellular structures make them highly susceptible to damage during standard freezing, preservation, and storage procedures—complicating the manufacturing, inventory management, and distribution required for commercial cell therapies.
Furthermore, obstacles persist even after the cells are administered to a patient. Fully mature macrophages frequently home in on and sequester themselves within filtering organs, such as the lungs and liver, rather than dispersing broadly throughout the body to target disseminated disease sites. Their relatively rapid clearance and disappearance from circulation can also severely restrict the duration and overall efficacy of the treatment.
Seeking to bypass these persistent biological and manufacturing limitations, the USC research team decided to pivot their strategy away from mature cells and focus instead on an earlier, more malleable stage of immune cell development.
Creating a Renewable Supply of Cancer-Fighting Immune Cells
Rather than attempting to manufacture massive quantities of fully differentiated, mature macrophages directly, first author Shi Yue, MD, working within Dr. Ying’s laboratory alongside his colleagues, concentrated their efforts on GMPs—the dedicated progenitor cells that naturally give rise to macrophages and related cell types.
The research team successfully engineered a precisely defined chemical cocktail and culture environment that allowed GMPs to survive, thrive, and multiply continuously for extended periods within the laboratory setting. Crucially, this specialized chemical formula prevented the progenitor cells from prematurely differentiating into mature immune cells, thereby preserving a stable, renewable population of precursors that could be banked and scaled up at will.
Even after undergoing extensive rounds of laboratory expansion, the expanded GMPs faithfully maintained the molecular signatures and surface markers that define their progenitor identity. Most importantly, when the chemical environment was subsequently altered, these cells readily retained their developmental plasticity, successfully maturing into fully functional macrophages and other related immune cells as needed.
This methodological breakthrough makes it theoretically possible to manufacture virtually limitless quantities of engineered immune cells from a standardized, continually renewable starting population, eliminating the need to repeatedly harvest, process, and prepare mature cells from individual patients for every single batch of treatment.
To validate the reproducibility and robustness of this new technique, the USC team partnered with independent collaborators in the laboratory of Ravi Majeti, MD, PhD, at Stanford University. The Stanford researchers independently demonstrated that GMPs could be successfully maintained over extended periods and efficiently engineered, providing crucial external validation for the reliability of the technique and its viability for future translational cell therapies.
Dr. Majeti, who serves as the Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, noted the broader implications of the findings: "This method for the expansion and engineering of GMPs opens the door to numerous translational applications, much like T cell expansion and engineering. We have already demonstrated engineering of these cells to drive multiple potent functions, and there is a lot more to be explored."
Engineering Immune Cells to Recognize and Attack Tumors
With a reliable and scalable supply of progenitor cells established, the research team next sought to determine whether these expandable GMPs could be successfully programmed to actively seek out and destroy cancer cells.
To achieve this, the scientists genetically modified the GMPs to express a chimeric antigen receptor, or CAR. This synthetic, engineered receptor equips the immune cells with a specialized sensor designed to recognize a specific molecular target displayed exclusively on the surface of cancer cells, thereby directing their destructive activity straight toward the tumor.
While CAR technology has already revolutionized modern oncology—most notably through the engineering of patient-derived T cells—the USC researchers are among the first to explore whether an analogous strategy could be successfully deployed using GMPs to generate engineered macrophages and other innate immune defenders on demand.
In addition to the CAR constructs, the scientists equipped a subset of the progenitor cells with an auxiliary immune-activating signal. This secondary modification was specifically designed to recruit, stimulate, and activate nearby host immune cells, including native T cells, helping to orchestrate a coordinated, multi-pronged immune attack against the tumor.
This added signaling capability offered another potentially vital clinical advantage. Experimental data showed that the modified cells remained functionally effective even when the genetic immune characteristics of the donor cells did not closely match those of the recipient.
This finding raises the exciting prospect of eventually developing standardized, off-the-shelf immunotherapy products manufactured in advance from healthy screened donors. Unlike current personalized cell therapies, which must be painstakingly manufactured individually using each patient’s own biological material—a process that is both costly and time-consuming—such off-the-shelf products could potentially be produced in large, uniform batches and kept ready for immediate administration to multiple patients in need.
Engineered Cells Slow Cancer Progression in Mice
Having successfully expanded and genetically engineered GMPs derived from both murine and human sources, the researchers advanced to testing the therapeutic potential of the cells in rigorous preclinical mouse models.
When administered to the test subjects, the engineered progenitor cells successfully homed to and established themselves within the bone marrow and other primary niches responsible for natural blood cell production. These internal environments provided ideal biological staging grounds where the surviving GMPs could continuously generate fresh supplies of engineered macrophages and related immune cells from within the body.
This represented a crucial departure from conventional therapies that rely exclusively on the infusion of mature, terminally differentiated macrophages. Instead of depending entirely on a finite population of infused cells that inevitably decline and disappear from circulation over a short period, the engrafted progenitors provided a self-sustaining, ongoing source of cellular replacements produced directly inside the host.
This unique internal replenishment strategy may help overcome the rapid clearance and short half-life that have historically hampered macrophage-based therapies, including various approaches evaluated in recent clinical trials.
To evaluate therapeutic efficacy, the researchers deployed the engineered cells in mouse models representing both aggressive blood cancers and difficult-to-treat solid tumors. In these controlled experiments, GMPs armed with CAR receptors successfully slowed disease progression across both categories of cancer.
Significantly, the therapeutic effects were markedly enhanced when the progenitor cells carried both the targeted CAR receptors and the secondary immune-activating signal. This synergistic combination substantially improved the treatment’s capacity to marshal a broader, more robust antitumor immune response within the host animals.
Although these preclinical findings are highly encouraging, researchers emphasize that the work remains in the laboratory stage. Substantial additional research, safety testing, and clinical trials will be required to establish whether engineered GMPs can be deployed safely and effectively in human patients, particularly if the cells are intended to engraft, persist, and continually manufacture immune defenders over extended therapeutic windows.
Potential Applications Beyond Cancer Treatment
Beyond the realm of oncology, the research team investigated whether their novel cellular expansion platform could be adapted to treat other complex medical conditions characterized by dysfunctional or deficient immune defenses.
In a separate series of experiments using mouse models, the investigators turned their attention to chronic granulomatous disease. This severe, inherited genetic disorder severely impairs the ability of specific immune cells to generate the reactive molecules required to kill harmful microbes. Individuals afflicted with this condition suffer from heightened vulnerability to severe, recurrent bacterial and fungal infections because their innate immune cells are fundamentally incapable of eliminating certain pathogens.
When the researchers administered engineered GMPs to mice exhibiting the genetic disorder, the transplanted progenitor cells successfully restored the animals’ biological capacity to combat and clear dangerous bacterial infections.
This promising result strongly suggests that renewable, genetically engineered immune cell progenitors could eventually find clinical applications far beyond cancer treatment, extending into the management of inherited primary immune deficiencies and potentially difficult-to-treat infectious diseases.
According to the study’s authors, the broader conceptual lesson of the research is that the developmental maturity stage of a therapeutic immune cell may be just as critical to treatment success as the specific genetic modifications engineered into it.
By intervening earlier in cellular development and engineering cells before they reach full maturity, scientists may unlock a new generation of cellular therapies that are simpler to manufacture, more adaptable, and capable of maintaining a sustained, self-renewing supply of specialized defenders inside the body.
"Our study suggests that the future of immunotherapy may depend not only on designing better CAR receptors, but also on choosing the right developmental stage of the cell," Dr. Ying concluded.
About the Research
The peer-reviewed study, titled "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy," was published in the scientific journal Cell.
The multidisciplinary research team included Qi-Long Ying, Shi Yue, Zheng Guo, Crystal Pan, Xueyuan A. Jing, Tai Nguyen, Jiaqi Tang, Yanpui Chan, Humberto Contreras-Trujillo, Du Jiang, Xue Yan, Hang Xiang, Xugeng Liu, Xiao Wang, Ziyuan Wang, Natalie Shu, Daniel B. McKim, Rong Lu, and Chao Zhang from the University of Southern California; Litao Tao and Celia Bloom from Creighton University; Asiri Ediriwickrema and Sebastian Koschade from the Stanford University School of Medicine; and Yingxiao Shi from Harvard Medical School and the Dana-Farber Cancer Institute.
Financial support for the investigation was provided by the Chen Yong Foundation of the Zhongmei Group, a sponsored research project grant from Myelogene Inc., the L.K. Whittier Foundation, the Eli and Edythe Broad Innovation Award, the Ming Hsieh Institute for Research on Engineering Medicine for Cancer Award, the USC SBIR/STTR Planning Award, the Xia Research Fund, and the Wu & Jiang Research Fund.
Additionally, Dr. Majeti reported receiving research support from the Ludwig Institute for Cancer Research, while co-author Zheng Guo received funding through a California Institute for Regenerative Medicine Predoctoral Training Fellowship.
