Blood Test Clue: Immune Cells That Betray Early Lung Cancer Before It Strikes

Lung cancer kills an estimated 1.8 million people every year, and by the time most patients are diagnosed, the disease has already advanced beyond the reach of curative treatment. Now, a large international study led by researchers at University College London has revealed a striking biological signature that appears in the blood long before invasive lung cancer takes hold — a discovery that could transform how doctors detect and even prevent one of the world’s deadliest malignancies. The work, published in Nature, maps a previously hidden network of immune suppression that operates across the bloodstream, lymph nodes and airways during the earliest stages of tumour development.

The research focused on non-small cell lung cancer, or NSCLC, the umbrella term for the most common forms of the disease, including lung squamous cell carcinoma and lung adenocarcinoma. Rather than studying established tumours, the team turned its attention to premalignant lesions — abnormal patches of tissue in the central airways that have not yet become cancerous. These lesions are routinely detected in high-risk smokers through a technique called autofluorescence bronchoscopy, in which special light reveals suspicious areas of the bronchial lining. The clinical stakes are considerable: while low-grade lesions rarely progress, between 50 and 80 per cent of high-grade lesions invade to become frank cancer within two to three years, making these patients an ideal population in which to test strategies for interception.

Using single-cell RNA sequencing on bronchial biopsies from patients under surveillance at University College London Hospitals, the researchers profiled thousands of individual T cells — the immune system’s principal assassins and regulators. Among the ten distinct T cell populations they identified, one stood out with unusual clarity: a subset of effector regulatory T cells, known as Treg cells, marked by high expression of a transcription factor called BATF. These BATF-positive Treg cells expressed the highest levels of FOXP3, CD25, CTLA-4 and a suite of highly suppressive molecules including OX40, GITR, 4-1BB and CCR8 — a molecular profile previously associated with aggressive tumours and poor responses to immunotherapy. Crucially, these cells were selectively and significantly enriched in high-grade premalignant lesions compared with normal tissue, while no other CD4 or CD8 T cell population showed a comparable increase. The immune system, in other words, was being actively disarmed before cancer had even invaded.

The team then asked where these suppressive cells came from. By sequencing T cell receptors — the unique molecular barcodes that identify individual T cell clones — in both lesions and matched blood samples, they uncovered a remarkable clonal connection. Nearly 18 per cent of all BATF-positive Treg cell clonotypes found in the lesions were also present in the peripheral blood, and the dominant blood population sharing these clonotypes was a circulating effector Treg cell population expressing CD39. Statistical modelling confirmed that this sharing was far greater than chance, with an odds ratio of nearly 39. Pseudotime analysis, which reconstructs cellular differentiation trajectories, suggested a blood-to-lung journey: circulating effector Treg cells appeared to migrate into the airways, where antigen-presenting cells displaying MHC class II molecules and engaging CD86–CTLA-4 and TNFSF9–TNFRSF9 interactions drove their activation, expansion and tissue adaptation.

This clonal link opened the door to something clinically transformative: a non-invasive blood test. In a cohort of 129 blood samples from 47 patients in the bronchoscopy surveillance programme, the researchers found that patients carrying high-grade lesions had significantly elevated frequencies of circulating CD39-positive effector Treg cells compared with those with only low-grade disease — a result that held even after adjusting for age, smoking history and previous cancer diagnosis. The signal extended to patients with established, screen-detected early-stage lung cancer as well. In the ASCENT study of patients diagnosed through CT screening, 90 per cent of whom had stage I disease, circulating effector Treg cells were significantly increased compared with healthy individuals. An independent validation cohort comparing 77 early-stage lung adenocarcinoma cases with 67 CT-screened individuals showing no signs of disease reproduced the finding with striking significance.

Perhaps most compelling was the longitudinal evidence. For a small group of patients who developed lung squamous carcinoma during CT surveillance, blood samples had been collected at three- to twelve-month intervals from enrolment to diagnosis. Deep sequencing of T cell receptors in these serial samples revealed a marked and progressive increase in effector Treg cell clonotypes from baseline to the moment of cancer diagnosis, while naive-like and central-memory Treg clones remained stable or changed only modestly. The rising immune signature was not a static correlate but a dynamic process tracking tumour development in real time. When the researchers combined the blood effector Treg frequency with the intratumoural BATF-positive Treg signature in 89 patients with clinical follow-up, they found that patients with high values on both measures faced a nearly fourfold increase in the hazard of recurrence or death — a risk that remained significant after adjustment for age, stage, sex, smoking status and technical batch effects.

To establish causality rather than mere correlation, the team turned to a mouse model in which the carcinogen NTCU induces lung squamous tumorigenesis that faithfully recapitulates the human disease, progressing from low-grade to high-grade dysplasia and finally to invasive carcinoma. The same cross-tissue effector Treg axis emerged: BATF-positive Treg cells accumulated selectively around the bronchial tree, shared clonotypes with circulating effector Treg cells, and were seeded partly from the blood. Upstream, the tumour-draining mediastinal lymph nodes showed elevated PD-L1 expression on migratory type 1 conventional dendritic cells — a change absent from non-draining lymph nodes — alongside an expansion of Treg cells. Blocking lymph node egress with the drug FTY720 sharply reduced both lung Treg cells and circulating effector Treg cells, confirming that the lymph node acts as a supply depot feeding the suppressive network. The conservation of this axis across species underscored its biological centrality to early lung carcinogenesis.

The therapeutic implications were tested directly. Because pathway analysis revealed heightened PI3K signalling in BATF-positive Treg cells, the researchers administered PI-3065, an inhibitor of the PI3K-delta enzyme that is known to preferentially impair Treg cell maintenance, starting at week 15 when preinvasive disease first appears. The results were dramatic: tumour incidence fell from 83 per cent to 42 per cent, and the tumours that did emerge were significantly smaller, with the largest 30 per cent eliminated entirely. A control inhibitor targeting the unrelated PI3K-alpha enzyme had no such effect. Spatial transcriptomics using the Xenium platform revealed the mechanism: carcinogenesis had spawned peribronchial immature tertiary lymphoid structures — dense immune aggregates rich in Treg cells, CXCL13-associated macrophages, germinal-centre-like B cells and specialized vasculature. PI3K-delta inhibition dismantled these structures, selectively depleting Treg cells while increasing conventional type 1 dendritic cells, effectively converting suppressive hubs into potential sites of immune surveillance. A complementary experiment with an anti-CD25 depleting antibody confirmed that Treg cells actively restrain CD8 T cell differentiation during high-grade dysplasia.

The authors propose a ‘theranostic’ framework in which circulating effector Treg cells serve multiple roles: as a non-invasive diagnostic for high-grade premalignant lesions, as an adjunct for risk-stratifying CT-detected nodules, as a pharmacodynamic readout during treatment, and as a tool for selecting patients for Treg-directed immunotherapy. Because immune interventions in people without invasive cancer demand an exceptionally high safety margin, the researchers suggest that next-generation PI3K-delta inhibitors with better toxicity profiles, intermittent dosing schedules, or delivery directly to the airway by inhalation or robotic bronchoscopy could minimize risk. They also acknowledge that specificity remains a challenge — chronic inflammation, infection and injury can all perturb Treg cell homeostasis — and propose pairing the immune signature with routine infection markers such as C-reactive protein, or using longitudinal monitoring to detect a rising rather than a merely elevated signal.

If validated at scale in prospective interception trials, this work could mark a turning point in lung cancer prevention. As CT screening programmes expand worldwide and identify ever more premalignant lesions, clinicians currently have limited tools to decide which patients need aggressive follow-up and which can be safely monitored. A simple blood test that reads the immune system’s own account of tumour development — and a drug strategy that dismantles the suppressive network before invasion begins — would give medicine something it has rarely possessed in oncology: the ability to stop cancer not by treating it, but by intercepting it on the way to becoming dangerous.

Subject of Research: A preinvasive regulatory T cell axis that tracks and can be targeted to intercept early lung squamous cancer development

Article Title: A preinvasive regulatory T cell axis for lung cancer interception

Article References: Gamble, S., Whiteman, Z. E., Peinador-Marín, C., Lebrusant-Fernandez, M., Shurr, A. Y. L., Enica, A., Sahwangarrom, T., Ung, S. K. A., Rogers, A., Fessas, P., Khaw, C. R., Kalinke, L., Ahlmann-Eltze, C., Alhendi, A. S. N., Otter, K., Hu, X., Thakkar, K., Gration, B., Newsham, I., … Reading, J. L. (2026). A preinvasive regulatory T cell axis for lung cancer interception. Nature. https://doi.org/10.1038/s41586-026-11066-6

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11066-6

Keywords: lung cancer, regulatory T cells, BATF, cancer interception, premalignant lesions, PI3K-delta inhibitor, immunotherapy, CT screening, tertiary lymphoid structures, single-cell sequencing, tumour immunology, early detection