Immune-cell study hints IL-1β macrophages may fuel pro-tumor signals in liver cancer

Researchers have mapped immune and stromal cell populations in hepatocellular carcinoma (HCC), one of the most lethal malignancies, and identified a subset of macrophages carrying the pro-inflammatory messenger IL-1β that appears to be linked to an inflammatory, tumor-promoting microenvironment. The study, published in Clinical Epigenetics, combines single-cell RNA sequencing, spatial transcriptomics and preliminary laboratory drug testing, though the authors stress that in-vivo functional validation is still required.

The team performed deep single-cell RNA sequencing on 37 tumor and paired paracancerous tissue samples collected from 20 patients with HCC. Based on the proportions of immune cells infiltrating the tumor microenvironment (TME), patients were stratified into two groups: an immune-excluded-like subtype (IES), in which T and B lymphocytes are largely kept out of the tumor, and an immune-infiltrated-like subtype (IIS), characterized by greater lymphocyte presence.

The profiling revealed that the two immune subtypes differ sharply in cellular composition. Compared with the IIS group, the TME of IES tumors was predominantly infiltrated by macrophages and stromal cells, accompanied by reduced infiltration of T and B lymphocytes. Within the IES group, the researchers identified a distinct IL-1β-positive macrophage subset with prominent pro-inflammatory signatures, suggesting that this cell population may help define the immune landscape of tumors that exclude cytotoxic lymphocytes.

Tumor-associated macrophages (TAMs) are known to be highly heterogeneous and to exert critical disease-related functions, but their diversity, functional states and regulatory roles within the HCC microenvironment have remained incompletely characterized. The new single-cell atlas addresses this gap by resolving macrophage and cancer-associated fibroblast (CAF) subsets that may be linked to tumor progression and to response to immunotherapy.

To connect the cell populations to spatial organization and candidate signaling, the researchers integrated published spatial transcriptomic datasets with their own multiplex immunofluorescence and single-cell RNA-seq data. These multi-omics analyses suggest potential crosstalk between IL-1β-positive macrophages and tumor cells via the PGE2–IL-1β axis, a signaling route that, according to the authors, might favor tumor progression. The researchers characterize this as a suggested mechanism rather than a demonstrated causal pathway, and the findings are framed as preliminary.

The study also characterized an inflammatory fibroblast subset, termed IL-1R1-positive iCAFs, whose molecular features are associated with impaired T-cell cytotoxicity and putative immunotherapy resistance. In preliminary in-vitro pharmacological observations, the team found hints that signals derived from IL-1β-positive macrophages could support pro-tumor properties of these inflammation-associated CAFs through the IL-1β/IL-1R1 axis, pointing to a possible macrophage-to-fibroblast communication route within the TME.

On the pharmacological side, in-vitro cellular assays were used to provide preliminary evidence for candidate signaling axes. The authors emphasize that these observations are early-stage: the conclusion of the study states that the multi-omics data highlight the putative role of IL-1β-positive macrophages in shaping a pro-tumor TME in HCC, and that preliminary pharmacological evidence points to the therapeutic potential of targeting the IL-1R1-positive iCAF subpopulation to improve immunotherapy outcomes, although in-vivo functional validation is still required.

Related open-access studies, including a single-cell atlas of the multicellular ecosystem of primary and metastatic HCC published in 2022 and analyses of immune subtypes based on immune-disorder-related lncRNAs, reflect an accelerating effort to dissect the TME at single-cell resolution. The present study adds a specific macrophage–fibroblast signaling axis to that map, linking inflammatory myeloid cells, IL-1R1-positive fibroblasts and diminished T-cell cytotoxicity in the immune-excluded subtype.

For clinicians and researchers, the practical significance lies in the identification of candidate targets. If subsequent in-vivo studies confirm the suggested roles of the PGE2–IL-1β axis and the IL-1β/IL-1R1 signaling route, intercepting these pathways could offer a strategy to reprogram the immune-excluded microenvironment and potentially improve responses to immunotherapy in a subset of HCC patients. For now, the findings stand as preliminary, multi-omics-based evidence that IL-1β-positive macrophages may contribute to inflammatory reprogramming of tumor cells and support pro-tumor features of IL-1R1-positive iCAFs in hepatocellular carcinoma.

Subject of Research: Single-cell and multi-omics analysis of IL-1β-positive macrophages and IL-1R1-positive inflammatory cancer-associated fibroblasts in the hepatocellular carcinoma tumor microenvironment

Article Title: IL-1β-positive macrophages may contribute to inflammatory reprogramming of tumor cells and support pro-tumor features of IL-1R1+iCAFs in hepatocellular carcinoma: preliminary pharmacological and multi-omics evidence

Article References: Wang, Y., Ma, P., Hu, H., Li, W., Lv, Z., & Zhang, X. (2026). IL-1β-positive macrophages may contribute to inflammatory reprogramming of tumor cells and support pro-tumor features of IL-1R1+iCAFs in hepatocellular carcinoma: preliminary pharmacological and multi-omics evidence. Clinical Epigenetics. https://doi.org/10.1186/s13148-026-02259-x

Image Credits: AI Generated

DOI: 10.1186/s13148-026-02259-x

Keywords: hepatocellular carcinoma, tumor microenvironment, tumor-associated macrophages, IL-1β, IL-1R1, inflammatory cancer-associated fibroblasts, single-cell RNA sequencing, spatial transcriptomics, PGE2–IL-1β axis, immunotherapy resistance, immune-excluded subtype, multi-omics