The scale of the resource is what sets it apart. Most previous single-cell RNA sequencing studies of human liver pooled relatively small numbers of cells from limited patient cohorts, which made it hard to resolve subtle transcriptional states relevant to disease. The new atlas integrates seven published studies into a single reference containing 649,295 cells drawn from 77 donors—42 with healthy livers and 35 with chronic liver disease, balanced across 38 males and 39 females. After rigorous quality control, iterative subclustering and manual annotation, the researchers organized the data into three hierarchical levels: 16 broad cell lineages, 34 intermediate cell types and, at the finest resolution, 125 transcriptionally distinct cellular states. The atlas even captured rare residents of the liver, including neurons, mast cells, basophils, neutrophils and hematopoietic progenitor cells, which individual studies had rarely described. An interactive web browser allows any researcher to query the gene expression profiles.

The analytical centerpiece concerns macrophages, the scavenger immune cells that both fuel and resolve fibrosis. Within 81,577 nonproliferating mononuclear phagocytes, the team distinguished tissue monocytes, conventional dendritic cells, resident Kupffer cells and, crucially, two separate populations of so-called scar-associated macrophages, or SAMacs—cells marked by the proteins TREM2, CD9, CD63 and SPP1 that previous work had implicated in activating the scar-producing myofibroblasts of the liver. Differential abundance testing with the Milo algorithm showed that both SAMac populations expand in diseased livers, but with a telling difference: SAMac2 expanded consistently across every etiology of chronic liver disease, whereas SAMac1 expansion was most pronounced in the biliary disorders primary biliary cholangitis and primary sclerosing cholangitis.

Why does splitting SAMacs into two matter? Because the field has been stuck in a contradiction. Some studies painted TREM2-positive scar macrophages as fibrosis drivers; others found that TREM2 and the SAMac molecule SPP1 actually carry anti-inflammatory and antifibrotic properties, promoting scar resolution. The new data dissolve the paradox by showing that the two SAMac populations are transcriptionally almost opposite. Differential expression analysis, run with a statistical hurdle model and Bonferroni correction, flagged 903 genes enriched in SAMac1 and 1,176 in SAMac2. SAMac1 expressed GPNMB along with a suite of reparative factors—MMP9, IL10, GDF15, CD36 and PPARG—resembling the lipid-associated macrophages described in mouse and human fatty tissue. SAMac2, by contrast, lit up with pro-inflammatory and pro-fibrotic mediators: IL1B, TNF, IL18, the inflammasome component NLRP3, AREG and PDGFB, plus the scavenger receptors OLR1 and CLEC5A. Flow cytometry confirmed expansion of TREM2-positive, OLR1-positive macrophages in diseased human livers, and immunofluorescence placed OLR1-positive CD68-positive cells precisely within fibrotic tissue.

Spatial context came from a 36-plex antibody panel run on the PhenoCycler-Fusion platform across 46 patient liver samples, spanning healthy tissue and explants or biopsies from metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease, PBC and PSC. Computational neighborhood analysis identified three cellular niches, one of them a fibrotic niche packed with fibroinflammatory cells and dense fibrillar collagen deposition that expanded dramatically in disease. Both OLR1-positive and GPNMB-positive macrophages preferentially accumulated inside that niche, yet they remained largely distinct from one another—occasional double-positive cells existed, but the two markers mostly labeled separate cells, mirroring the single-cell data and confirming genuine macrophage heterogeneity at the site of scarring.

The clinical stakes became clear when the team turned to outcome data. In liver needle biopsies from MASLD patients, SAMacs expanded and upregulated OLR1, which stayed macrophage-specific. Then, mining the SteatoSITE multimodal database of 632 histologically staged MASLD cases, the researchers found that hepatic OLR1 expression correlated positively with fibrosis stage and with other fibroinflammatory genes, and negatively with markers of homeostatic Kupffer cells and sinusoidal endothelial cells. Deconvolution of bulk RNA-sequencing data using the single-cell reference showed both SAMac populations rising with fibrosis stage, a pattern replicated in independent cohorts of MASLD, PSC, ARLD and PBC patients. Most strikingly, in the longitudinal SteatoSITE cohort, high OLR1 expression and high estimated SAMac2 abundance were both associated with increased all-cause mortality and faster progression to hepatic decompensation—the point at which a scarred liver stops coping.

Cross-species work strengthened the case. In mouse models of fibrosis induced by carbon tetrachloride, bile duct ligation and a choline-deficient high-fat diet, the team found the same two Trem2-positive SAMac subpopulations, with the Olr1-positive counterpart again enriched for inflammatory genes including Il1b and Nlrp3. Both populations expanded during active injury and returned to baseline once injury ceased, tracking fibrogenic activity in time as well as space. Flow cytometry showed that Olr1-positive SAMacs produced more interleukin-1 beta than their CD319-positive SAMac1 counterparts. Bone-marrow chimera experiments established that both subpopulations arise from circulating monocytes rather than resident Kupffer cells. Single-cell ATAC-sequencing added a chromatin dimension: Olr1-positive SAMac2 carried open chromatin enriched for pro-inflammatory transcription factor motifs—Fos, Jun, NF-kB and Rel family members—while SAMac1 showed motifs linked to interferon responses and regulatory factors, indicating the two states are epigenetically primed for different jobs.

Ligand-receptor modeling with the LIANA and Tensor-cell2cell frameworks then predicted how each SAMac population talks to the mesenchymal cells that manufacture collagen. SAMac1’s outgoing signal repertoire contained recognized antifibrotic factors such as HGF, IGF1, MMP9 and GDF15. SAMac2’s contained TNF, TGFB1, IL1B, IL18, complement C3 and PDGFB—mediators associated with promoting fibrogenesis. Functional tests followed. Conditioned media from human monocyte-derived macrophages with OLR1 knocked down by siRNA were less able to induce collagen gene expression in LX2 stellate cells, and treatment with MEDI6570, a clinically tested OLR1-blocking antibody, similarly dampened fibrillar collagen expression. In a three-dimensional multilineage spheroid model of MASH—primary hepatocytes, macrophages and stellate cells challenged with lipotoxic free fatty acids—OLR1 knockdown reduced fibrogenic activity and abolished fibrillar collagen protein production. The team also showed that a chronic inflammatory stimulus cocktail (TNF, prostaglandin E2 and Pam3CSK4) pushed macrophages toward the SAMac2 program, whereas fatty acids and glucocorticoids pushed toward the SAMac1-like state.

The therapeutic implication is unusually concrete, because OLR1—also known as LOX-1, a class E scavenger receptor—already has a drug-development history in cardiovascular medicine, where it has been implicated in atherosclerosis, cardiac fibrosis and cancer biology. MEDI6570 has been administered to patients in phase 1 and phase 2 trials, raising the prospect of repurposing it, or developing small-molecule OLR1 inhibitors, for liver disease. The authors caution that much remains to be learned: the activating ligands of OLR1 in the injured liver, whether macrophages can switch between the SAMac1 and SAMac2 states, and whether OLR1 can serve as a predictive biomarker all require further study. They also note that hepatocytes and stellate cells are better captured by single-nucleus approaches, and that candidate targets from single-cell studies must be validated in independent, histologically staged biopsy cohorts—as OLR1-positive SAMacs were here. Still, by resolving the heterogeneity that had made scar macrophages such a confusing target, the atlas converts a paradox into a plan: spare the reparative macrophages, silence the inflammatory ones, and perhaps finally slow the scarring that ends so many livers.

Subject of Research: Single-cell transcriptomic identification of OLR1-positive scar-associated macrophages as a therapeutic target in chronic liver disease fibrosis

Article Title: A human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease

Article References: Papachristoforou, E., Kong, K., Colella, F., Tam, J., Luft, J., Parhar, R., Liang, Y., McCafferty-Brown, A., Finney, G., Rao, K., Ravichandar, J. D., Sutherland, E. F., Veizades, S., Grzelka, M., Qiu, P. K., Asif, A., Battle, I., Hammer, M., Kuschnereit, T., … Ramachandran, P. (2026). A human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease. Nature Genetics, 58(10), 2550-2565. https://doi.org/10.1038/s41588-026-02774-w

Image Credits: AI Generated

DOI: 10.1038/s41588-026-02774-w

Keywords: single-cell RNA sequencing, liver fibrosis, macrophages, OLR1, chronic liver disease, scar-associated macrophages, TREM2, MASLD, spatial proteomics, antifibrotic therapy, Nature Genetics, liver atlas

OLR1, also known as LOX-1, was first characterized decades ago as an endothelial receptor that binds oxidized low-density lipoprotein, the modified cholesterol particles implicated in atherosclerosis. In the years since its discovery, accumulating evidence has linked the receptor to cancer biology in multiple tumor types, where it has been associated with poor outcomes, immune suppression, and the behavior of myeloid-derived suppressor cells. Until now, however, its precise contribution to gastric cancer and, crucially, its influence on the tumor microenvironment remained poorly defined. The new study was designed to close that gap by combining large-scale clinical data analysis with laboratory experiments probing both the function and the mechanism of OLR1 in gastric cancer cells.

To establish the clinical relevance of the receptor, the team mined The Cancer Genome Atlas, a comprehensive public repository of genomic and clinical data from cancer patients. Their analysis revealed that OLR1 is significantly upregulated in gastric cancer tissue compared with healthy tissue, and that elevated expression correlates with unfavorable prognosis. In practical terms, patients whose tumors expressed high levels of the receptor tended to fare worse, suggesting that OLR1 is not merely a passenger alteration but a biologically meaningful marker of aggressive disease. The researchers then validated these findings experimentally in gastric cancer cell lines, confirming that the patterns observed in patient data are reflected in the molecular behavior of the tumor cells themselves.

With the correlation established, the investigators turned to gain- and loss-of-function experiments to determine whether OLR1 actively drives malignancy or merely accompanies it. When they forced gastric cancer cells to overproduce the receptor, the cells became more prolific: proliferation and migration both increased, and tumors grew faster in animal models. Conversely, when OLR1 was silenced or knocked down, these malignant behaviors were curtailed. These complementary approaches, conducted both in vitro and in vivo, provide strong evidence that OLR1 is a functional driver of gastric cancer progression rather than a passive biomarker. The in vivo assays were conducted under protocols approved by the Committee of Experimental Animal Ethics of Nanjing Medical University, and the findings together paint a coherent picture of a receptor that empowers tumor cells to divide, move, and expand.

The most consequential part of the study, however, lies in its mechanistic findings. Cancer rarely advances through tumor cell autonomy alone; it depends heavily on co-opting the surrounding microenvironment, a complex ecosystem of immune cells, stromal cells, blood vessels, and signaling molecules. Within this ecosystem, macrophages occupy a pivotal position. These innate immune cells are remarkably plastic, capable of adopting radically different functional states. The M1 phenotype is generally inflammatory and antitumoral, while the M2 phenotype is immunosuppressive, wound-healing oriented, and, in the context of cancer, protumorigenic. Tumors rich in M2-polarized macrophages tend to suppress cytotoxic T cell activity, remodel tissue architecture to favor invasion, and resist immunotherapy.

Using a series of mechanistic assays, Chen, Wang, and colleagues demonstrated that OLR1 promotes the polarization of macrophages toward this immunosuppressive M2 phenotype. In other words, gastric cancer cells carrying high levels of the receptor do not merely grow faster on their own; they actively recruit and reprogram the immune cells around them to become allies of the tumor. This reprogramming contributes to a protumorigenic microenvironment in which the normal immune surveillance that might otherwise eliminate malignant cells is blunted. The finding aligns with a growing body of literature showing that tumor-associated macrophages are among the most important non-malignant players in cancer progression and that lipid metabolism and lipid-sensing receptors can shape macrophage behavior.

The second mechanistic pillar of the study concerns a signaling pathway familiar to almost every cancer biologist: nuclear factor kappa B, or NF-κB. This transcription factor family governs inflammation, cell survival, and immune responses, and its chronic activation is a hallmark of many tumors, including those of the gastrointestinal tract. The researchers found that OLR1 activates NF-κB signaling in gastric cancer cells, and that this activation underlies the tumor-promoting behaviors they observed. The connection is biologically plausible: prior work has shown that LOX-1 engagement can trigger NF-κB-dependent inflammatory signaling in other cell types, including microglial cells under hypoxic conditions, and NF-κB is well established as a regulator of cytokine production and immune modulation within the tumor microenvironment. By tying OLR1 to NF-κB activation in gastric cancer, the study links a lipid-sensing receptor to one of the central inflammatory engines of malignancy.

The convergence of these two mechanisms, NF-κB activation within tumor cells and M2 macrophage polarization within the microenvironment, offers a compelling explanation for why high OLR1 expression portends poor outcomes. A tumor that simultaneously accelerates its own growth and dismantles the immune response against it gains a decisive survival advantage. Importantly, the authors propose that OLR1 could serve not only as a prognostic biomarker, helping clinicians identify patients at higher risk of aggressive disease, but also as a therapeutic target. If OLR1 activity can be pharmacologically blocked, the dual benefits of restraining tumor cell proliferation and restoring a more favorable immune contexture might be achievable. Anti-LOX-1 strategies have already been explored in the cardiovascular field, where the receptor is a recognized player in atherosclerotic disease, providing a potential pharmacological starting point for oncology applications.

The study also situates itself within a broader and rapidly evolving research landscape. Recent work has implicated a variety of tumor-derived signals, including complement components such as C4BPA acting through the C5a-C5aR1-STAT3 axis, the cytokine subunit INHBA acting through PI3K/AKT signaling, and exosomal microRNAs, in driving M2 macrophage polarization in gastric cancer. Metabolic reprogramming, particularly of lipid metabolism, has emerged as a recurring theme in how tumors shape macrophage behavior, and OLR1’s identity as a receptor for oxidized lipids fits squarely within this framework. The findings may also help explain why gastric cancer frequently resists immunotherapy: tumors can deploy multiple, redundant mechanisms to polarize macrophages toward a suppressive state, and effective interventions may need to target these pathways in combination.

Supported by funding from the Changzhou Science and Technology Bureau and Nanjing Medical University, the research represents a step toward precision oncology for gastric cancer, a disease in which the identification of clinically actionable biomarkers remains an urgent unmet need. As with any preclinical study, translation to the clinic will require additional validation, including studies of OLR1 blockade in robust animal models and, ultimately, clinical trials. Nevertheless, by demonstrating that a single receptor can simultaneously fuel tumor-intrinsic aggressiveness through NF-κB and orchestrate immune evasion through macrophage polarization, the work provides a mechanistically grounded rationale for pursuing OLR1 as both a marker of poor prognosis and a point of therapeutic attack. For a cancer that remains a leading cause of cancer-related mortality worldwide, such dual-purpose targets are precisely the kind of molecular leverage points that the field has been searching for.

Subject of Research: The role of the OLR1 receptor in gastric cancer progression via NF-κB activation and M2 macrophage polarization

Article Title: OLR1 drives gastric cancer progression through NF-κB activation and immunosuppressive macrophage polarization

Article References: Chen, Z., Wang, Y., Xu, X., Zhao, M., & Zhou, X. (2026). OLR1 drives gastric cancer progression through NF-κB activation and immunosuppressive macrophage polarization. Medical Oncology, 43(10), Article 275. https://doi.org/10.1007/s12032-026-03394-4

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03394-4

Keywords: OLR1, gastric cancer, NF-κB signaling, macrophage polarization, tumor microenvironment, M2 macrophages, biomarker, immunosuppression, cancer progression, Medical Oncology, drives, gastric