The landmark finding, detailed in a study published in the prestigious scientific journal Cell, addresses and potentially overcomes some of the most persistent and formidable obstacles currently facing modern cancer immunotherapy. Among these historical hurdles are the extreme difficulty of manufacturing a sufficient quantity of therapeutic immune cells on demand and the challenge of keeping those cells active, viable, and effective once inside the human body. In rigorous experimental trials involving mice, these newly engineered cells successfully established themselves within the bone marrow, continuously produced fresh populations of functional immune cells, and demonstrably slowed the progression of both aggressive blood cancers and stubborn solid tumors.
Led by a dedicated team of investigators at the USC Stem Cell initiative, the research specifically focused on a specialized class of immature immune precursors known as granulocyte-monocyte progenitors, or GMPs. In normal biological development, these progenitor cells eventually mature into macrophages and other crucial immune cells that protect the host body from dangerous infections and coordinate complex immune responses. However, the USC team uncovered a surprising and previously unrecognized characteristic of these cells: GMPs could be grown extensively in laboratory cultures while successfully retaining their intrinsic capacity to develop into fully functioning immune cells later. Furthermore, they proved remarkably receptive to precise genetic modifications, allowing scientists to program them to recognize specific cancer markers and amplify broader, systemic immune reactions.
"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," explained 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 and highly promising applications in the ongoing war against cancer, the discovery fundamentally challenges long-standing biological paradigms regarding how blood and immune cells develop and differentiate over time.
Within the scientific community, stem cells have long been celebrated for their remarkable ability to self-renew, a biological property that allows them to divide repeatedly while meticulously preserving their original, uncommitted properties. Within the mammalian blood-forming system, this crucial self-renewal capacity has traditionally been attributed almost exclusively to hematopoietic stem cells, the master progenitors capable of giving rise to every major type of blood and immune cell found in the body.
Progenitor cells, by sharp contrast, occupy a more advanced position along the developmental assembly line. Because they are already committed to producing a much more limited, restricted range of descendant cells, they were historically believed to possess a severely diminished capacity for long-term self-renewal.
Yet, the USC research team successfully demonstrated that under carefully optimized and strictly controlled laboratory conditions, GMPs can defy these conventional expectations and retain this vital self-renewal ability. Instead of rapidly maturing into terminal cell types and exhausting their population, the progenitor cells continued multiplying exponentially while meticulously preserving their unique cellular identity and their underlying capability to generate functional immune cells upon demand.
"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 noted. "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 transformative for the development of advanced medical treatments that require massive, highly reliable, and reproducible supplies of genetically customized immune cells to mount an effective therapeutic defense.
Why Macrophages Could Be Powerful Weapons Against Cancer
To understand the practical significance of the discovery, it is essential to examine the unique role played by macrophages within the human immune system. Recognized as some of the body’s most versatile defenders, their name is derived from Greek etymology meaning "big eaters," a descriptive moniker that highlights their exceptional ability to actively surround, engulf, and neutralize invading bacteria, cellular debris, and other foreign or damaged materials.
Beyond their cleanup duties, macrophages actively coordinate complex immune responses by secreting chemical signals that directly influence the behavior and activation status of neighboring immune cells. Certain specialized populations of macrophages are naturally inclined to infiltrate the microenvironment of tumors and actively attack malignant cancer cells, making them extraordinarily attractive candidates for the development of innovative cancer immunotherapies.
One particularly compelling application lies in the treatment of solid tumors—cancers that form dense, physical masses within vital organs and tissues. While existing cell-based therapies utilizing engineered T cells have achieved unprecedented clinical successes against certain liquid blood cancers, tackling solid tumors has historically proven vastly more difficult due to the immunosuppressive barriers erected by the tumor microenvironment.
Macrophages offer a potentially revolutionary alternative approach because they naturally migrate deep into bodily tissues and possess an innate ability to penetrate solid tumor masses. However, translating this biological reality into practical, bedside treatments has presented formidable logistical and scientific challenges.
Once macrophages reach their fully mature state, they become notoriously difficult to multiply in large, commercially viable quantities outside the living body. Furthermore, mature macrophages are remarkably resistant to standard genetic modification techniques and are frequently damaged or destroyed during traditional freezing, preservation, and storage processes, severely complicating the large-scale industrial production and global distribution of such cell-based therapies.
An additional obstacle routinely manifests after the therapeutic cells are administered to a patient. Fully mature macrophages frequently sequester themselves in filtering organs such as the lungs and the liver rather than dispersing widely throughout the body to find scattered disease sites. Moreover, their relatively rapid disappearance from circulation often limits how long a treatment remains clinically effective.
Determined to circumvent these persistent limitations, the USC research team decided to bypass the mature stage altogether and initiate their therapeutic interventions much earlier in the developmental lineage of the immune system.
Creating a Renewable Supply of Cancer-Fighting Immune Cells
Rather than attempting the arduous task of manufacturing massive quantities of mature macrophages, the research team—led by first author Shi Yue, MD, working within Dr. Ying’s laboratory—focused their attention squarely on GMPs, the committed progenitor cells that serve as the direct biological precursors to macrophages.
The investigators engineered a precisely balanced, chemically defined growth mixture that allowed GMPs to survive, thrive, and multiply continuously for extended periods within laboratory bioreactors. This specialized chemical environment successfully prevented the progenitor cells from prematurely differentiating into mature immune cells, thereby preserving a robust, highly renewable population of active precursors.
Even after undergoing extensive rounds of laboratory expansion, the expanded GMPs faithfully maintained the complex molecular characteristics that defined their progenitor status. Most importantly, when introduced to the appropriate biochemical signals, they retained their full functional capacity to develop rapidly into operational macrophages and other related, disease-fighting immune cells.
This breakthrough strategy could ultimately make it possible to manufacture industrial quantities of engineered immune cells derived from a continuous, highly stable starting population, eliminating the need to repeatedly harvest, process, and prepare mature cells from individual patients for every single treatment cycle.
To rigorously confirm that the methodology was robust and universally reproducible, 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 for prolonged periods and accurately engineered using genetic tools, providing vital external validation for the reliability of the technique and its immense translational potential for future clinical cell therapies.
Dr. Majeti, who serves as the Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, emphasized the broad implications of the work: "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 secured, the research team turned their investigative focus toward programming these expandable cells to actively seek out and destroy cancer.
The scientists genetically modified the GMPs to express a synthetic chimeric antigen receptor, widely known as a CAR. This specialized, engineered receptor equips the immune cells with a molecular radar system capable of identifying specific, predetermined protein markers displayed exclusively on the surface of cancer cells, thereby directing their aggressive locomotor and phagocytic activity straight toward malignant tumors.
While CAR technology has already revolutionized modern oncology—most notably through therapies that genetically modify a patient’s own T cells to hunt down leukemia and lymphoma—the USC researchers pioneered the application of this sophisticated strategy to GMPs, enabling the generation of customized, CAR-expressing macrophages and related immune defenders.
Furthermore, to enhance the potency of the treatment, the scientists equipped a subset of the progenitor cells with an additional, engineered immune-activating signal. This secondary modification was specifically designed to recruit, stimulate, and rally nearby endogenous immune cells, including native T cells, to join the fray and mount a coordinated, multi-pronged assault against the cancer.
This clever secondary enhancement offered another profound clinical advantage: the modified signaling mechanism remained fully effective even when the major histocompatibility markers of the donor cells did not precisely match those of the recipient patient.
This critical observation raises the exciting possibility of developing standardized, "off-the-shelf" immunotherapies utilizing cells manufactured well in advance from healthy screened donors. Unlike traditional personalized cell therapies—which require custom laboratory preparation utilizing each individual patient’s unique biological material—such universal products could theoretically be produced in large, economical batches and kept ready on pharmacy shelves for immediate administration to multiple patients.
Engineered Cells Slow Cancer Progression in Mice
Following the successful laboratory expansion and genetic engineering of both murine and human GMPs, the research team advanced their investigations to evaluate the therapeutic efficacy of the cells in live animal models.
When administered to mice, the engineered progenitor cells successfully homed in and established themselves firmly within the bone marrow and other primary niches responsible for natural blood cell production. These hospitable biological microenvironments provided a steady, sustaining home where the GMPs could continuously manufacture fresh supplies of engineered macrophages and related immune defenders from within the animal’s own body.
This represented a profound operational departure from conventional therapies utilizing mature macrophages. Rather than depending entirely on a finite injection of mature immune cells that typically degrade and disappear from circulation within a short timeframe, the progenitor-based approach provided a self-sustaining, ongoing source of cellular replacement parts generated directly inside the host.
This internal replenishment strategy effectively solves the rapid-clearance dilemma that has historically frustrated macrophage-based therapies, including various experimental approaches evaluated in recent clinical trials.
When tested rigorously in mouse models afflicted with both aggressive blood cancers and stubborn solid tumors, the engineered GMPs carrying CAR receptors successfully slowed disease progression across both categories of malignancy. The therapeutic benefits were even more pronounced when the progenitor cells were armed with the dual combination of CAR receptors and the secondary immune-recruiting signal, which synergistically enhanced the treatment’s ability to orchestrate a broad, systemic antitumor response.
Despite these undeniably encouraging preclinical milestones, the researchers emphasize that the findings remain strictly at the laboratory stage. Substantial further research, extensive safety profiling, and rigorous clinical trials will be absolutely necessary to establish whether engineered GMPs can be deployed safely and effectively in human patients, particularly given the ambition of allowing them to persist and continuously generate immune cells over extended therapeutic windows.
Potential Applications Beyond Cancer Treatment
Looking beyond oncology, the scientific team also investigated whether their adaptable progenitor platform could be leveraged to treat other complex medical conditions characterized by severe defects in the body’s natural immune defenses.
In a separate set of controlled mouse experiments, the researchers turned their attention to chronic granulomatous disease, a debilitating inherited genetic disorder that critically impairs the ability of specific immune cells to generate the reactive oxygen species needed to kill harmful invading microbes. Individuals afflicted with this condition suffer from extreme vulnerability to recurrent, severe, and frequently life-threatening bacterial and fungal infections because their native immune cells cannot effectively eliminate certain pathogens.
When the investigators administered their engineered GMPs to mice afflicted with the genetic disorder, the therapeutic cells successfully restored the animals’ physiological ability to fight off dangerous bacterial infections.
This striking outcome strongly suggests that renewable, genetically engineered immune cell progenitors could eventually find diverse medical applications far beyond cancer treatment alone, potentially paving the way for advanced therapies targeting hereditary primary immune deficiencies and persistent infectious diseases.
According to the researchers, the overarching lesson of the study is that the precise developmental stage chosen for cellular engineering may ultimately prove just as critical to therapeutic success as the genetic modifications themselves. By intervening and engineering immune cells upstream before they reach terminal maturity, scientists may unlock a new generation of treatments that are drastically easier to manufacture, structurally more adaptable, and biologically capable of maintaining a continuous, self-renewing supply of specialized cellular defenders.
"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 pioneering study was published in the journal Cell under the formal title "Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy."
The multi-institutional research effort was spearheaded by 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; alongside Litao Tao and Celia Bloom from Creighton University; Asiri Ediriwickrema and Sebastian Koschade from the Stanford University School of Medicine; and Yingxiao Shi representing Harvard Medical School and the Dana-Farber Cancer Institute.
Financial backing for the project was provided by the Chen Yong Foundation of the Zhongmei Group, a sponsored research initiative funded by 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. Additional support was received by Dr. Majeti from the Ludwig Institute for Cancer Research, while researcher Zheng Guo was supported through a California Institute for Regenerative Medicine Predoctoral Training Fellowship.