A comprehensive research investigation published in Nature Cancer demonstrates that basophils actively suppress early lung metastatic seeding in experimental models by restricting regulatory T cells and promoting antitumor CD8+ T cell responses. Working across murine tumor models and human patient cohorts, an international research team led by Nahal Mansouri revealed that these rare white blood cells, historically recognized primarily for mediating allergic responses and host defense against parasites, exert an unexpected antimetastatic function. Through single-cell RNA sequencing of lungs bearing subcutaneous 4T1 mammary carcinoma micrometastases, investigators observed pronounced alterations in the local immune landscape, including an expansion of basophils alongside neutrophils and monocyte-macrophages, accompanied by a decline in regulatory T cells. Utilizing selective basophil depletion via the monoclonal antibody Ba103 targeting CD200R3 in mice injected intravenously with fluorescently labeled 4T1 mammary carcinoma cells or Kras-mutant and p53-null lung adenocarcinoma cells, the authors established that the absence of basophils significantly augmented early cancer cell seeding in pulmonary tissue. Furthermore, microcomputed tomography and histological analysis revealed that basophil elimination markedly increased metastatic burden and nodule counts, whereas the adoptive transfer of donor basophils reduced lung seeding, establishing that basophils serve as active inhibitors of early pulmonary dissemination.

The antimetastatic activity of basophils depends directly on their capacity to restrain immunosuppressive regulatory T cells, which typically safeguard developing metastases by dampening cytotoxic immune responses. Experimental basophil depletion led to a rapid and pronounced accumulation of CD4+FOXP3+ regulatory T cells within both the spleen and pulmonary tissue of tumor-bearing and tumor-free animals, whereas basophil transfer diminished regulatory T cell numbers. Gene expression profiling through single-cell RNA sequencing showed that regulatory T cells from basophil-depleted lungs exhibited elevated expression of Foxp3 and Stat5a alongside activation-associated transcriptional signatures, including enriched MYC target, mTORC1, and interleukin-2-STAT5 signaling cascades. Direct cellular examination using time-lapse microscopy and confocal immunofluorescence in reporter mice visualized frequent basophil-Treg physical clusters across systemic circulation, splenic tissue, draining lymph nodes, and primary and metastatic tumor sites. In primary ex vivo cocultures of murine splenocytes and bone marrow-derived basophils, the presence of basophils induced apoptosis in regulatory T cells and abrogated their ability to suppress CD8+ T cell proliferation.

Dissecting the molecular machinery underlying this cellular restraint revealed two complementary pathways, the first of which operates through basophil-secreted histamine targeting histamine H1 receptors. Transcriptomic analysis of lung-infiltrating basophils identified marked upregulation of the gene encoding histidine decarboxylase, the primary enzyme responsible for histamine synthesis, while interrogations of human and mouse immune datasets confirmed that regulatory T cells predominantly express the HRH1 receptor over other histamine receptor subtypes. When basophils were cocultured with regulatory T cells, single-cell sequencing identified broad suppression of classical regulatory T cell signatures and an elevation of proapoptotic caspase pathways and mitochondrial superoxide production, measured via MitoSOX fluorescence. Crucially, loratadine did not alter basophil viability, activation status, or histamine secretion itself, confirming that basophil-derived histamine acts directly upon the regulatory T cell compartment through HRH1 to undermine regulatory cell stability and promote programmed cell death.

Pharmacological blockade of histamine signaling in animal disease models substantiated the critical role of HRH1 in restraining regulatory T cells and restricting metastatic colonization. Daily oral administration of loratadine to mice challenged intravenously with either 4T1 mammary or Kras-Tp53-mutant lung carcinoma cells caused a moderate expansion of circulating and splenic FOXP3+ regulatory T cells, mirroring effects achieved using diphenhydramine. This elevated immunosuppressive state accelerated cancer cell dissemination in the lung parenchyma, as quantified by both fluorescence microscopy and flow cytometric assessment of disseminated tumor cells. Concurrently, loratadine administration diminished the proportion of cytotoxic granzyme B-positive CD8+ T cells infiltrating the lungs and circulation. Transcriptional profiling of sorted splenic immune subsets confirmed that loratadine-treated regulatory T cells upregulated survival pathways, whereas splenic CD8+ T cells exhibited marked downregulation of proliferation markers such as Mki67 and key cytotoxic effectors, including granzyme A and granzyme B. Conversely, in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis where regulatory T cell activity is therapeutically advantageous, oral loratadine treatment significantly reduced neurological clinical deficit scores and accelerated functional recovery, highlighting how the histamine-HRH1 axis dynamically controls regulatory T cell potency in different pathological contexts.

In parallel to soluble histamine release, basophils deploy a contact-dependent mechanism driven by mast cell protease 8, which enzymatically cleaves interleukin-2 receptor alpha, also known as CD25, on regulatory T cells. During in vitro coculture experiments, basophils induced a near-complete loss of cell-surface CD25 within four hours, an effect that was entirely abolished when cells were physically separated using transwell culture inserts. Capillary-based automated western blotting demonstrated that while total CD25 transcript and protein abundance remained unchanged, exposure to basophils produced an approximate 10-kilodalton reduction in CD25 molecular mass, shifting from 71 to 61 kilodaltons and indicating extracellular proteolytic cleavage. Screening candidate protease classes established that the serine protease inhibitor AEBSF preserved CD25 molecular integrity and surface expression, whereas cysteine and aspartyl protease inhibitors showed no protective efficacy. Small interfering RNA-mediated knockdown targeting Mcpt8 in basophils reversed CD25 degradation, whereas knocking down the related protease Prss34 failed to rescue the receptor. Combining loratadine with AEBSF generated additive restorative effects on CD8+ T cell proliferation, establishing that contact-mediated CD25 cleavage and diffusible HRH1 signaling act concurrently to destabilize regulatory T cell function.

Spatial transcriptomic and histological evaluations of intact pulmonary tissue confirmed that this contact-dependent proteolytic regulation occurs actively within living mammalian tissues. In lungs from Foxp3-reporter mice and transgenic lung adenocarcinoma models, high-resolution immunofluorescence and spatial transcriptomic maps documented physical proximity between MCPT8-positive basophils and regulatory T cells. Detailed proximity analyses established that regulatory T cells located within 50 micrometers of a basophil displayed markedly lower surface CD25 immunoreactivity and diminished IL-2-STAT5 pathway scores compared to regulatory T cells located farther away. To determine the relative immunological impact of these interactions, the authors formulated a mechanistic ordinary differential equation model simulating coculture kinetics and mass-action cell dynamics. The computational simulations revealed that while direct basophil-mediated killing of regulatory T cells confers antitumor benefits, relieving regulatory T cell-mediated suppression of CD8+ cytotoxic T cells represents the predominant mechanism driving overall cancer cell destruction. When both direct cytotoxicity and suppression relief were modeled simultaneously, their combined effects operated additively, demonstrating that disabling regulatory T cell inhibitory functions is essential for restoring robust cytotoxic lymphocyte responses against newly arrived disseminated malignant cells.

Basophil trafficking and functional licensing within the pulmonary microenvironment are coordinated by defined molecular cues derived from resident alveolar macrophages and local immunoglobulins. Computational cell-cell communication modeling using NicheNet identified the chemokine CCL24 as the foremost ligand driving basophil recruitment into tumor-bearing lung tissues, showing elevated expression within macrophages and dendritic cells. High-resolution spatial imaging localized CCL24-positive alveolar macrophages directly adjacent to basophils along the invasive tumor margin, while enzyme-linked immunosorbent assays revealed elevated CCL24 concentrations in bronchial aspirates collected from individuals with lung cancer compared to cancer-free controls. Upon reaching the tissue, basophils undergo activation characterized by surface-bound immunoglobulin E crosslinking via Fc-epsilon receptor I. Basophils primed with interleukin-3 released substantial quantities of histamine and mast cell protease 8 following anti-IgE stimulation or exposure to lung carcinoma-conditioned medium, triggering enhanced CD25 cleavage and boosting tumor cell lysis by cytotoxic lymphocytes. Single-cell profiling of lung-infiltrating basophils confirmed enriched signatures of immunoglobulin E-dependent activation, indicating that endogenous humoral responses collaborate with macrophage-derived chemokines to license basophil antimetastatic effector functions.

Crucial aspects of the basophil-regulatory T cell axis were found to be conserved in human biology, including an intracellular signaling pathway that governs HRH1 expression. Immunofluorescence staining of healthy human lung, spleen, and non-small cell lung cancer specimens verified physical basophil-Treg clustering, while reanalysis of human single-cell datasets uncovered an inverse correlation between basophil and regulatory T cell frequencies. In human ex vivo cocultures, basophils moderately reduced regulatory T cell viability and suppressed conserved activation gene networks, which was reversed by loratadine. Mechanistically, T cell receptor stimulation with anti-CD3/CD28 beads upregulated HRH1 expression in human regulatory T cells across multiple time points, mediated by downstream mitogen-activated protein kinase signaling through the transcription factor ELK1. Pharmacological inhibition of this cascade using the MEK inhibitor trametinib markedly reduced ELK1 and HRH1 expression in stimulated regulatory T cells without altering FOXP3, confirming that T cell receptor-driven MAPK signaling licenses HRH1 expression. Furthermore, pan-cancer transcriptomic analyses from The Cancer Genome Atlas revealed that elevated expression of histidine decarboxylase correlated significantly with superior disease-specific survival across multiple human solid malignancies.

To directly assess whether type 1 antihistamines alter regulatory T cell dynamics in people, the investigators conducted a prospective, randomized, double-blind, crossover clinical trial involving 40 healthy adult volunteers. Registered under clinical trial identifier IRCT20170608034390N14, the human study enrolled male and female participants aged 20 to 30 years who were assigned to receive either 10 milligrams of daily oral loratadine followed by placebo or the reverse sequence for 21 days per period without washout. Following complete protocol monitoring and accounting for study dropouts, flow cytometric analysis of peripheral blood mononuclear cells from 30 placebo-treated and 29 loratadine-treated sampling timepoints was conducted. The trial demonstrated a statistically significant increase in the frequency of circulating CD4+CD25+ regulatory T cells following loratadine administration compared with placebo, whether evaluated across treatment periods or within paired crossover analyses. No adverse events were reported among study participants during the intervention windows. These prospective human trial findings directly corroborated the observations made in murine models and isolated primary cell cultures, confirming that pharmacological blockade of the HRH1 receptor elevates systemic regulatory T cell prevalence in healthy human subjects.

Finally, multiomic profiling across mouse models and clinical datasets revealed that basophils transition between two evolutionarily conserved transcriptional programs during malignant progression. By integrating quantitative mass spectrometry proteomics from circulating murine basophils with multiple single-cell transcriptomic datasets from murine models and human colorectal, breast, and non-small cell lung cancers, the researchers delineated a steady-state quiescent B0 program comprising 12 genes and a tumor-associated B1 program defined by 10 genes. Basophils in healthy tissues exhibited predominant B0 programming, whereas tumor-infiltrating basophils progressively shifted toward the B1 phenotype, upregulating type 2 cytokines such as interleukin-4 and interleukin-13. Although B1 basophils retained their capacity to cleave CD25 and restrain regulatory T cells, their conditioned medium prompted bone marrow-derived macrophages to undergo M2-like polarization marked by increased CD206 and arginase 1 expression.

Subject of Research: Basophil regulation of regulatory T cells and early lung metastasis

Article Title: Basophils inhibit early lung metastasis by suppressing regulatory T cells

Article References: Torchia, B., Fournier, N., Yücel, S., Fournier, M., Setareh, S., Esmaily, H., Mohammadzadeh, Y., Lourenco, J., Ghasemi, A., Marcandalli, E., Li, L., Mesdaghi, M., Namazi Bayegi, S., Faust, C., Schule, A. M., Scolaro, T., Manco, M., Wyser Rmili, C., Ubags, N., … Mansouri, N. (2026). Basophils inhibit early lung metastasis by suppressing regulatory T cells. Nature Cancer. https://doi.org/10.1038/s43018-026-01257-5

Image Credits: AI Generated

DOI: 10.1038/s43018-026-01257-5

Keywords: Cancer Research, Immunology, Metastasis, Basophils, Regulatory T Cells, Oncology, Histamine, Immunotherapy, inhibit, early, lung, suppressing