More than thirty years ago, the U.S. Food and Drug Administration (FDA) made a landmark decision by approving Bacillus Calmette-Guérin (BCG) as the first immunotherapy for cancer treatment. Since then, BCG has remained a cornerstone therapy for early-stage bladder cancer, setting the stage for the development of modern cancer immunotherapies. Despite its longstanding use, the precise biological mechanisms underlying BCG’s anti-cancer effects have eluded full scientific comprehension. A groundbreaking study by researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK) now elucidates how BCG not only acts locally but also induces systemic immune modulation via the bone marrow, offering fresh insights that could revolutionize cancer immunotherapy approaches.
BCG is derived from a weakened strain of the bacterium Mycobacterium bovis, originally developed as a vaccine against tuberculosis and administered extensively to children worldwide. In bladder cancer therapy, however, BCG is introduced into the bladder at much higher concentrations. Traditionally, its mechanism was thought to rely on direct infection of cancer cells, which would then attract and activate immune cells to target the tumor. This paradigm suggested a localized immune activation. Yet, until now, the full spectrum of immune responses triggered by BCG, especially the systemic facets, remained inadequately explored.
Dr. Michael Glickman, a physician-scientist and acting director of the Marie-Josée Kravis Center for Cancer Immunobiology at MSK, emphasized how BCG stands as a classic example of a treatment validated by clinical outcomes long before its molecular and cellular underpinnings were understood. His team’s recent publication in Cancer Cell reveals that beyond its local bladder effects, BCG reprograms hematopoietic stem and progenitor cells (HSPCs) within the bone marrow. This reprogramming bolsters the generation of myeloid cells—a crucial subset of innate immune cells—thereby amplifying the body’s broader immune competence against tumors.
This expansion of the innate immune response is particularly significant because the innate immune system serves as the body’s first responder, offering rapid and generalized defense mechanisms. Unlike the adaptive immune system—which relies on prior exposure and develops highly specific responses—innate immunity can provide an immediate antitumor effect. The study demonstrates that BCG’s immunotherapeutic benefit partly arises from its ability to enhance this innate arm of immunity, essentially “training” bone marrow progenitors to yield immune cells better equipped to detect and destroy cancer cells.
The investigative team combined meticulous analyses of blood samples from bladder cancer patients undergoing BCG therapy with advanced studies using mouse models of bladder cancer. Leveraging a sophisticated technique known as Progenitor Input Enrichment single-cell sequencing (PIE-seq), developed at Weill Cornell Medicine, the researchers could deeply profile rare circulating HSPCs from patients’ blood draws. This innovative approach bypassed the need for more invasive bone marrow biopsies and provided unprecedented insights into cellular reprogramming following BCG treatment.
Findings revealed significant shifts in gene expression within these progenitor cells, indicating that BCG therapy redefines the developmental trajectory of immune cells in the bone marrow. The newly programmed myeloid cells emerging from these progenitors displayed enhanced tumor-fighting capacities, supporting the concept that BCG acts systemically, far beyond the bladder, to orchestrate a refined innate immune response.
Complementing their patient data, mouse model studies established that BCG bacteria administered intravesically could translocate from the bladder to the bone marrow, where live bacteria could be cultured. This observation decisively confirmed that BCG acts not just as a local stimulus but also as a systemic immunomodulator. Consistent with prior observations of BCG vaccination reducing susceptibility to viral infections, the researchers postulate that BCG’s capacity to prime bone marrow progenitors underlies broad immune benefits extending beyond cancer therapy.
The research also explored therapeutic synergies between BCG and checkpoint inhibitors, another class of immunotherapy that functions by lifting inhibitory signals on T cells, thus reigniting their ability to recognize and attack tumors. Mouse experiments demonstrated that combining BCG with checkpoint inhibitors resulted in superior tumor shrinkage and prolonged survival compared to either therapy alone. This synergy arises because BCG-stimulated myeloid cells enhance T cell activation, effectively creating a mutually reinforcing immune environment for cancer eradication.
Dr. Steven Josefowicz, associate professor of pathology and laboratory medicine at Weill Cornell Medicine and co-senior author on the study, noted that these findings have profound implications for the future of cancer immunotherapy. They suggest that strategically targeting the bone marrow to reprogram innate immunity can substantially augment the efficacy of existing treatments. This strategy might open avenues for improving immunotherapies across various cancer types, fostering immune resilience at the fundamental cellular level.
Despite the promising nature of these discoveries, several questions remain. Future research will need to address how best to harness and optimize this bone marrow reprogramming therapeutically and whether intravesical administration of BCG can potentiate immunotherapy responses in cancers beyond the bladder. As Dr. Glickman remarks, while these concepts are compelling, translating them into clinical practice requires careful, rigorous investigation.
This study was made possible by the extensive collaboration between clinical scientists and researchers, supported by ongoing collection of patient samples through MSK urologic surgeon Dr. Eugene Pietzak, as well as contributions from McGill University. The multidisciplinary nature of this research exemplifies the integration of clinical insights with cutting-edge molecular techniques necessary to unlock the complexities of cancer immunotherapy.
In conclusion, this research reinvigorates our understanding of BCG as not just a bladder-specific treatment but as a potent systemic immune trainer. By revealing the pivotal role of the bone marrow in mediating BCG’s effects, it opens new horizons for designing therapies that not only attack tumors directly but also harness the body’s intrinsic defense architectures for sustained and enhanced cancer control.
Subject of Research: Cancer immunotherapy; BCG therapy; innate immunity; hematopoietic stem and progenitor cells; bone marrow reprogramming; bladder cancer
Article Title: BCG Immunotherapy Reprograms Bone Marrow Progenitors to Enhance Innate Immunity Against Cancer
News Publication Date: 29-May-2025
Web References:
- https://www.mskcc.org/cancer-care/types/bladder/treatment/bacillus-calmette-guerin-therapy
- http://dx.doi.org/10.1016/j.ccell.2025.05.002
- https://www.sciencedirect.com/science/article/pii/S0092867423007961?via%3Dihub
References: The publication in Cancer Cell, May 29, 2025
Keywords: Immunology; Cancer immunotherapy; Medical treatments; Innate immune system; BCG therapy; Hematopoietic stem cells; Bone marrow; Bladder cancer; Checkpoint inhibitors
