Pericyte-like cells may help shape the immune landscape of glioblastoma

Glioblastoma remains one of the most formidable challenges in modern oncology, and a growing body of research suggests that part of the answer to its resilience lies not in the tumor cells themselves but in the cellular entourage that surrounds them. A new study published in Experimental & Molecular Medicine examines a specific and previously underappreciated population of stromal cells within these tumors: fibroblast activation protein-positive, or FAP-positive, pericyte-like cells. According to the research, these cells appear to play an active role in steering incoming monocytes toward becoming tumor-associated macrophages, the immunosuppressive workhorses that glioblastomas deploy in abundance to shield themselves from immune attack.

Tumor-associated macrophages and microglia collectively constitute one of the largest immune cell populations in glioblastoma, often accounting for up to a third of the total cellular mass of the tumor. Unlike the inflammatory macrophages that would normally sweep into tissue to destroy pathogens or clear damaged cells, macrophages residing inside glioblastomas adopt a profoundly tumor-supportive identity. They secrete growth factors that stimulate tumor cell proliferation, remodel the extracellular matrix in ways that ease invasion, suppress cytotoxic T cell activity, and blunt the effectiveness of immunotherapies that have transformed the treatment of many other cancers. Understanding where these macrophages come from, and what forces shape their immunosuppressive character, has therefore become a central question in neuro-oncology.

The prevailing view has long been that tumor-associated macrophages in the brain arise from two principal sources. The first is the resident microglia, the innate immune cells native to the central nervous system, which become corrupted by tumor-derived signals. The second is circulating monocytes, produced in the bone marrow, which are recruited across the disrupted blood-brain barrier and then differentiate into macrophages within the tumor microenvironment. The new study focuses on this second pathway and asks a deceptively simple question: what cellular intermediaries in the tumor decide that an incoming monocyte should become a macrophage, and what kind of macrophage it becomes?

The answer, the researchers report, involves a population of pericyte-like stromal cells that express fibroblast activation protein, a membrane-bound serine protease that has served for decades as a marker of activated fibroblasts in wound healing and in the desmoplastic stroma of many solid tumors. Pericytes are mural cells that normally wrap around blood vessel endothelial cells, stabilizing vasculature and helping to maintain the blood-brain barrier. In glioblastoma, however, the study indicates that a subset of these pericyte-like cells acquires FAP expression and, with it, a striking new function: the ability to promote the differentiation of monocytes into macrophages with a tumor-associated phenotype.

Technically, the investigators combined single-cell transcriptomic analysis with functional assays to dissect this interaction. Single-cell RNA sequencing allows researchers to profile the gene expression of thousands of individual cells within a tumor, revealing not only the identity of rare cell populations but also the signaling ligands and receptors they deploy. By mapping the communication networks among tumor cells, macrophages, and stromal compartments, the team was able to identify FAP-positive pericyte-like cells as a hub of immunomodulatory signaling. In co-culture experiments, these cells were shown to drive monocytes toward a macrophage fate, biasing the resulting cells toward the immunosuppressive, pro-tumoral polarization that characterizes tumor-associated macrophages in glioblastoma.

The clinical implications of this finding are considerable. Glioblastoma has proven stubbornly resistant to immune checkpoint inhibitors, the antibody therapies that unleash T cells against melanoma, lung cancer, and many other malignancies. One widely cited explanation is that the glioblastoma microenvironment is saturated with immunosuppressive macrophages and microglia that actively paralyze T cells. If FAP-positive pericyte-like cells are among the architects of this immunosuppressive army, then targeting them, or the signals they use to educate monocytes, could represent a way to thin the ranks of tumor-associated macrophages and thereby open a window for T cell-based immunotherapy to function.

Fibroblast activation protein itself is an appealing therapeutic target. It is minimally expressed in healthy adult tissues but abundant in activated stromal cells across multiple cancers, which has already made it the focus of antibody-drug conjugates, small-molecule inhibitors, and radioligand imaging agents in ongoing clinical trials elsewhere in oncology. The demonstration that FAP marks a functionally important stromal population within glioblastoma raises the possibility that strategies developed for pancreatic, breast, and colorectal cancers could be adapted to brain tumors, although the blood-brain barrier and the infiltrative nature of glioblastoma present formidable delivery challenges that any such approach would need to overcome.

Beyond therapy, the study adds an important conceptual layer to the evolving understanding of the glioblastoma microenvironment. Pericytes have traditionally been studied for their roles in vascular biology: they regulate capillary diameter, contribute to blood-brain barrier integrity, and scavenge cellular debris. The idea that a pericyte-derived population can act as an immune educator, converting myeloid precursors into tumor-promoting macrophages, underscores how fluid the functional boundaries are between the vascular, stromal, and immune compartments of a tumor. It also helps explain why glioblastomas are so consistently and comprehensively immunosuppressive: the tumor appears to recruit or reprogram multiple cell types, including structural cells of its own vasculature, into a coordinated anti-immune apparatus.

There remain important questions for future work. The precise molecular signals by which FAP-positive pericyte-like cells induce monocyte differentiation, whether through secreted cytokines such as colony-stimulating factors, direct cell-cell contact, or remodeling of the extracellular matrix, will determine which points in the pathway are most druggable. It will also be essential to establish how these cells are themselves generated, whether they represent a distinct developmental lineage or a pathological reprogramming of ordinary pericytes, and whether their abundance correlates with patient outcomes, treatment resistance, or response to emerging immunotherapies. Longitudinal studies in patient cohorts and validation in additional model systems will be needed to translate the mechanism into prognostic and therapeutic tools.

Nevertheless, the study offers a vivid illustration of how modern single-cell biology is dismantling the old picture of tumors as homogeneous masses of malignant cells. Glioblastoma emerges instead as an ecosystem, one in which tumor cells, immune cells, vascular cells, and stromal cells engage in continuous negotiation, with each population reshaping the others for the tumor’s benefit. Identifying FAP-positive pericyte-like cells as promoters of macrophage differentiation adds a new node to this ecosystem map, and with it, a new set of potential targets. For patients facing a disease with a median survival measured in months despite surgery, radiation, and chemotherapy, every new node represents a new opportunity, and this one connects two of the most immunologically important cell types in the tumor. The hope, shared across the field, is that disrupting this stromal-immune axis could finally give immunotherapy a foothold in one of medicine’s most stubborn cancers.

The distinction between microglia and monocyte-derived macrophages has become increasingly tractable in recent years thanks to advances in single-cell and fate-mapping techniques. Microglia carry a transcriptional signature shaped by their embryonic origin and lifelong residence in the central nervous system, while recruited macrophages retain markers of their bone marrow lineage. Being able to separate these populations reliably matters therapeutically, because the two compartments respond differently to environmental cues and may require different intervention strategies. The identification of a stromal intermediary that actively shapes the monocyte-derived arm adds a layer of specificity to this growing taxonomy.

Pericyte plasticity is itself an area of intense investigation. In models of tissue injury, pericytes can detach from vessels, adopt migratory and secretory behaviors, and participate in scar formation. Similar programs appear to be activated within tumors, where aberrant signaling from malignant cells and from the disrupted vasculature may push pericytes into states that diverge substantially from their physiological roles. The acquisition of fibroblast activation protein expression by pericyte-like cells in glioblastoma fits this broader pattern of stromal remodeling, suggesting that the tumor co-opts a wound-healing-like program for its own purposes.

It is also worth noting that the monocyte-to-macrophage transition is not a single step but a continuum, with intermediate cells that retain plasticity. Signals encountered during recruitment and early differentiation can lock in long-lasting epigenetic programs, meaning that brief exposure to stromal factors may have durable consequences for macrophage behavior. This temporal sensitivity creates potential intervention windows: if the educational signal from FAP-positive cells can be interrupted early, the resulting macrophages might never adopt their tumor-supportive identity.

Finally, the convergence of stromal biology and immunology reflected in this work mirrors a trend across oncology, where cancer-associated fibroblasts and other stromal elements are increasingly recognized as active participants in immune evasion rather than passive scaffolding, reinforcing the case for combination approaches that target both malignant and stromal compartments.

Subject of Research: FAP-positive pericyte-like cells promoting monocyte differentiation into tumor-associated macrophages in glioblastoma

Article Title: FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma

Article References: Houdova Megova, M., Shard, C., Vymolova, B., Ternerova, N., Svablova, T., Buna, T., Straka, D., Vanickova, Z., Krepela, E., Kupcova Skalnikova, H., Kolar, M., Sachova, J., Kubovciak, J., Balaziova, E., Vymola, P., Hrabal, P., Ebert, L. M., Patil, A., Tomas, R., … Sedo, A. (2026). FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01827-8

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01827-8

Keywords: glioblastoma, tumor-associated macrophages, pericytes, FAP, monocytes, tumor microenvironment, immunosuppression, single-cell sequencing, immunotherapy, neuro-oncology, pericyte-like, cells