The findings emerge from an unusually comprehensive technical arsenal. The researchers combined multiplex immunohistochemistry, which stains multiple proteins simultaneously on tissue sections, with spatial analysis algorithms that map the physical distances between different cell types. They layered on top of this single-cell transcriptomics, which reads the gene expression profiles of individual cells, and chromatin-accessibility profiling, which reveals which genes are poised for activation in each cell. Perturbation models in mice, including genetic silencing of Itln1, allowed the team to test whether the correlations they observed in human tissue reflected true causal mechanisms rather than mere statistical associations.

In treatment-naïve human colorectal cancer samples, the researchers found that patients whose tumors expressed higher levels of ITLN1 had a distinctly different immune landscape. These tumors harbored greater numbers of infiltrating neutrophils, and critically, the mature neutrophils — identified by the co-expression of S100A9 and CXCR2 — sat significantly closer to ITLN1-positive tumor epithelial cells. This spatial intimacy was not incidental. Patients with this pattern of dense, well-positioned mature neutrophils survived longer than those whose tumors lacked ITLN1 expression and the accompanying neutrophil organization.

The mouse experiments transformed these human correlations into a mechanistic narrative. When the researchers silenced Itln1 in colorectal cancer models, tumors grew faster and spread more aggressively to distant sites. The silencing impaired the generation of mature CXCR2-positive, CD101-positive neutrophils in the bone marrow and reduced their recruitment into the tumor. In their place, immature neutrophils marked by LTF and S100A9 accumulated preferentially in hypoxic regions — the oxygen-starved zones within tumors where immature myeloid cells often suppress rather than support immune attack.

The mechanism the team uncovered reads like a molecular relay race spanning multiple organs. ITLN1, produced by epithelial cells in the gut, activates a JAK1/STAT3 signaling pathway that subsequently engages C/EBPδ, a transcription factor that governs the final stages of granulopoiesis — the process by which neutrophils mature from precursor cells in the bone marrow. This ITLN1–STAT3/C/EBPδ axis drives terminal granulopoiesis and upregulates CXCR2, the chemokine receptor that mature neutrophils use to home toward tumors. The result is a cross-tissue communication system in which an epithelial signal from the gut reaches the bone marrow and instructs it to produce and dispatch fully armed, tumor-killing neutrophils.

Perhaps the most therapeutically exciting result came from the team’s rescue experiments. When the researchers administered recombinant ITLN1 — the purified protein produced in the laboratory — to mice with silenced Itln1, neutrophil maturation was restored and the tumor-killing activity of these cells returned. This suggests that ITLN1 is not merely a biomarker that correlates with better outcomes but a functional agent that, if delivered, could reprogram the immune environment of colorectal tumors.

The study challenges a long-standing oversimplification in tumor immunology. Neutrophils have historically been cast as villains in cancer biology — suppressive cells that promote metastasis and dampen effective anti-tumor responses. This work adds crucial nuance by demonstrating that the same cell type can be a potent anti-cancer weapon when it reaches full maturity and is positioned correctly within the tumor architecture. The distinction between helpful and harmful neutrophils, the researchers suggest, may hinge on their maturation state and spatial relationship to tumor cells rather than on their mere presence or absence.

The spatial dimension of the findings carries particular weight in the era of cancer immunotherapy. Checkpoint inhibitors, which unleash T cells against tumors, have transformed treatment for melanoma and lung cancer but have shown limited efficacy in colorectal cancer, particularly in the microsatellite-stable subtype that accounts for the majority of cases. The identification of an epithelial-derived signal that governs neutrophil positioning opens a parallel therapeutic avenue that does not rely on T cells. If mature neutrophils can be recruited and organized within tumors through ITLN1 or drugs that mimic its downstream effects, this could complement existing immunotherapies or offer an alternative for patients whose tumors do not respond to checkpoint blockade.

The researchers acknowledge that the work was performed in treatment-naïve samples and mouse models, and that translating these findings into clinical practice will require further validation. Nonetheless, the identification of a cross-tissue axis linking gut epithelial ITLN1 to bone marrow granulopoiesis and tumor neutrophil organization represents a conceptual advance in understanding how the body’s first-line immune cells are mobilized against cancer. As the field moves toward spatially resolved, multi-omic profiling of tumors, studies like this one demonstrate that where a cell sits — not just what it is — may be the key to unlocking the next generation of cancer treatments.

Subject of Research: ITLN1, a gut epithelial protein, suppresses colorectal cancer by orchestrating neutrophil maturation and spatial anti-tumor immunity via a JAK1/STAT3–C/EBPδ–CXCR2 axis.

Article Title: ITLN1 suppresses colorectal cancer progression by orchestrating neutrophil maturation and spatial organization

Article References: Chen, L., Zhai, X., Chen, S., Luo, J., Sun, J., Qiao, G., Yang, C., Zhang, Y., Lou, X., Kou, M., Guo, L., Li, Z., Xie, D., Hu, Z., & Lian, Q. (2026). ITLN1 suppresses colorectal cancer progression by orchestrating neutrophil maturation and spatial organization. Nature Communications. https://doi.org/10.1038/s41467-026-78599-2

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78599-2

Keywords: colorectal cancer, ITLN1, intelectin-1, neutrophils, tumor immunology, cancer microenvironment, granulopoiesis, JAK-STAT signaling, C/EBPδ, CXCR2, spatial biology, single-cell transcriptomics

The team, led by immunologist Susanna Mandruzzato of the Veneto Institute of Oncology and the University of Padua, focused on a family of cells known as myeloid-derived suppressor cells, or MDSCs. These immature cells of the myeloid lineage, which includes precursors of granulocytes and monocytes, are best known from cancer research, where they accumulate in tumors and suppress the T cell responses that would otherwise attack malignant tissue. But MDSCs are not exclusive to cancer. They expand during infection, sepsis, and chronic inflammatory diseases, and recent work has implicated them in bone pathologies ranging from osteoporosis to inflammatory arthritis, where they can even act as dysfunctional osteoclast progenitors that contribute directly to bone destruction.

What made the question urgent for osteoarthritis is the disease’s peculiar inflammatory profile. Hip osteoarthritis is not an autoimmune condition like rheumatoid arthritis, yet it features a persistent, smoldering inflammation marked by elevated levels of cytokines such as IL-1β, TNF-α, and IL-6 in the joint environment. This inflammatory milieu promotes synovial activation, disrupts subchondral bone remodeling, enhances osteoclast formation, and accelerates cartilage breakdown through catabolic enzymes like metalloproteinases. In parallel, aging itself drives a phenomenon called inflammaging, a chronic low-grade inflammatory state that biases hematopoietic stem cells in the bone marrow toward producing myeloid cells at the expense of lymphoid lineages. The Padua team asked whether these two forces, aging and disease-associated inflammation, converge in the bone marrow of osteoarthritis patients.

To find out, the researchers collected fresh bone marrow aspirates from 13 patients undergoing total hip arthroplasty for osteoarthritis and 13 patients undergoing surgery for proximal femoral fracture, all recruited at the University-Hospital of Padova. The samples were drawn from the medullary canal of the femur during the earliest stage of surgical preparation, before any broaching of the canal, ensuring that the cellular composition reflected the living marrow environment. Patients with active malignancies, autoimmune diseases, infections, or hematological disorders were excluded. The two cohorts were not identical: the fracture patients were, on average, older than the osteoarthritis group, a difference the authors acknowledge as a potential confounder, but it makes the direction of their key finding all the more remarkable.

Using multiparametric flow cytometry, the team quantified the myeloid and lymphoid compartments in each sample. Despite being younger on average, the osteoarthritis patients showed a significantly higher proportion of myeloid cells in their bone marrow than the fracture patients, a difference that reached statistical significance at p = 0.0036. Lymphoid cell frequencies, by contrast, did not differ between the groups. This selective myeloid enrichment could not be explained by advanced age alone, suggesting that the chronic inflammation associated with hip osteoarthritis actively amplifies the age-related skewing of hematopoiesis toward the myeloid lineage. In other words, the disease may be superimposing its own inflammatory signature on top of the normal immunological remodeling of aging.

The researchers then drilled down into the maturation stages of these myeloid cells, using the surface markers CD11b and CD16 to distinguish granulocytic precursors at different points along their developmental path. Here a specific subset stood out. Cells with a CD11b-positive, CD16-low phenotype, which correspond to metamyelocytes, an intermediate stage of granulocyte maturation, were significantly enriched in the osteoarthritis samples, both when analyzed directly ex vivo and after the cells were cultured for four days with the growth factors G-CSF and GM-CSF to drive myeloid expansion. After cytokine stimulation, this metamyelocyte-like fraction reached a median of 31.5 percent in the osteoarthritis cultures versus 20.3 percent in the fracture cultures, a persistent difference indicating that the osteoarthritic marrow environment favors the production of these intermediate myeloid cells even under standardized laboratory conditions.

The functional heart of the study, however, lay in the suppressive capacity of these cells. In earlier work, the same group had established that the immunosuppressive power of bone marrow-derived MDSCs resides almost entirely in the most immature fraction, a CD11b-negative or low, CD16-negative population with promyelocyte-like features. In the new experiments, the researchers co-cultured these myeloid fractions with T cells from healthy donors that had been labeled with a fluorescent proliferation dye and activated with anti-CD3 and anti-CD28 antibodies. The result was unambiguous: only the immature fraction significantly inhibited T cell proliferation, in both osteoarthritis and fracture samples, while the more differentiated CD11b-positive fractions and unsorted bulk cultures had little or no effect. Suppression was accompanied by a marked downregulation of CD3 expression on the T cell surface, a well-established indicator of impaired T cell receptor signaling.

Crucially, the degree of suppression did not differ between the two patient groups. Even though the osteoarthritic marrow was more myeloid-skewed and richer in intermediate metamyelocyte-like cells, the core immunoregulatory machinery of the immature MDSC fraction remained intact and functionally equivalent to that of the fracture donors. This extends the team’s earlier observation that MDSC suppressive function is preserved during aging, from comparisons between pediatric and elderly donors, into the specific context of chronic osteoarthritis-associated inflammation. Morphological analysis by May-Grünwald-Giemsa staining of sorted populations confirmed the phenotypic story: the suppressive CD11b-low fraction showed uniform promyelocyte-like morphology with prominent nucleoli, while the more mature fractions contained myelocytes, metamyelocytes, band cells, and even macrophage-like cells with cytoplasmic vacuolation.

The authors are careful to frame these findings as an association rather than proof of a disease-specific mechanism. The fracture cohort, they note, is not a healthy control group; femoral fracture triggers its own acute, time-limited inflammatory response, and no ethically defensible route exists for harvesting bone marrow from truly healthy elderly volunteers. Differences in age and sex distribution between the cohorts, along with the modest sample size, particularly for the correlation analyses, further limit statistical power. The study also did not assess whether the osteoarthritic MDSCs can differentiate into osteoclasts, a question of obvious importance given evidence from breast cancer and inflammatory arthritis models that MDSCs can drive pathological bone resorption while simultaneously suppressing T cells. Whether the same dual function operates in hip osteoarthritis remains an open question for future work.

Even with those caveats, the study reframes osteoarthritis as a systemic immunological condition rather than a purely local joint disease. If the bone marrow of osteoarthritis patients is chronically pumping out expanded myeloid populations, those cells could feed the synovial inflammation, cartilage degradation, and aberrant subchondral bone remodeling that characterize disease progression, while their preserved suppressive activity simultaneously holds immune activation in check. The authors suggest this balance between heightened myelopoiesis and conserved immunoregulation may define the distinctive low-grade, persistent inflammatory state of osteoarthritis, setting it apart from overt autoimmune arthritis. It also raises a therapeutic possibility worth taking seriously: modulating myeloid responses, rather than broadly suppressing the immune system, might one day offer a way to slow joint degeneration in the elderly without compromising host defense. For a disease affecting hundreds of millions of people worldwide and currently treatable only with pain management and, ultimately, joint replacement, that would be a genuinely transformative shift in perspective.

Subject of Research: Bone marrow myeloid cell remodeling and myeloid-derived suppressor cell function in elderly patients with hip osteoarthritis

Article Title: Bone marrow myeloid skewing and preserved immunoregulation in hip osteoarthritis of elderly patients

Article References: Tushe, A., Binatti, E., Belluzzi, E., Pozzuoli, A., Francescato, S., Buldini, B., Biz, C., Ruggieri, P., & Mandruzzato, S. (2026). Bone marrow myeloid skewing and preserved immunoregulation in hip osteoarthritis of elderly patients. GeroScience. https://doi.org/10.1007/s11357-026-02578-0

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02578-0

Keywords: hip osteoarthritis, bone marrow, myeloid-derived suppressor cells, inflammaging, myelopoiesis, immunosenescence, T cell suppression, osteoimmunology, flow cytometry, granulopoiesis, chronic inflammation, GeroScience

The team, led by Yuman Wang and Teding Chang, assembled publicly available and newly generated datasets spanning the lung, heart, brain, vasculature, peripheral blood, intestine, kidney, and liver. After quality control and integration using reciprocal principal component analysis, the atlas comprised 66 samples and 256,949 cells. The compositional analysis revealed a striking pattern: neutrophil abundance rose markedly in several aged tissues. In the liver, the proportion of neutrophils among captured cells climbed from 0.75 percent in young mice to 5.26 percent in old ones; in the lung it rose from 0.88 to 4.14 percent; in vascular tissue from 1.05 to 3.68 percent; and in the intestine from 1.22 to 3.57 percent. The brain, shielded by the blood–brain barrier, showed no comparable increase.

These numbers were not artifacts of sequencing. Immunofluorescence staining for CD11b and myeloperoxidase confirmed dense neutrophil infiltration in aged lung, intestine, vasculature, and liver, while flow cytometry of bone marrow revealed a higher proportion of neutrophils in aged animals. A Bayesian compositional method called scCODA, which treats each biological sample as the unit of inference, independently supported a credible age-associated increase in neutrophil abundance in the liver, with a log2 fold change of 2.61 and an inclusion probability of 0.968.

Functionally, the aged neutrophils looked different at the molecular level. Pseudobulk differential expression analysis, which aggregates cells by sample to avoid inflating statistical significance, identified 26 genes upregulated in neutrophils from aged mice and 985 enriched in young ones. Gene set enrichment showed that glycolysis and reactive oxygen species pathways were activated in the aged cells, while TNF-α and interferon-λ signaling dominated in young ones. When the researchers isolated bone marrow neutrophils and cultured them for four hours, cells from aged mice died more readily and formed more neutrophil extracellular traps—web-like structures of DNA and antimicrobial proteins that, when deployed excessively, can damage surrounding tissue.

The most provocative experiments involved conditioned medium. When culture fluid from aged neutrophils was applied to mouse vascular smooth muscle cells and hepatocytes, both cell types showed increased beta-galactosidase activity, a classic marker of cellular senescence, along with elevated expression of matrix metalloproteinases and senescence-associated proteins such as P16 and P21. Quantitative PCR further revealed increased expression of senescance-associated secretory phenotype genes, including Il6, Tnf, and Ifn, in the exposed cells. In other words, factors released by aged neutrophils appeared to nudge tissue cells toward a stress-associated, inflammatory state.

To dissect neutrophil heterogeneity, the team re-clustered 5,210 neutrophils into 16 transcriptionally distinct subtypes, ranging from TNF-α-producing inflammatory cells to complement-associated, IL-6-expressing, E2F-driven, and unfolded-protein-response states. Several subtypes were preferentially enriched in aged mice, including Neu05-Complement, Neu06-IL6, and Neu08-E2F, while Neu01-TNFA and Neu04-Myc characterized young animals. Maturation scoring suggested that Neu05 and Neu08 resembled early marrow-emigrant neutrophils, mapping closest to the preNeu developmental stage, hinting that aged tissues may be receiving a wave of immature, hyper-responsive cells.

Cross-tissue co-occurrence analysis added a systems-level dimension. The researchers identified seven cellular modules whose member cell types varied in concert across samples. One module, CM3, was the most neutrophil-enriched and contained endothelial cells and fibroblasts alongside aged-enriched neutrophil states, suggesting that neutrophil accumulation covaries with stromal remodeling. CellChat-based ligand–receptor modeling predicted that aged endothelial cells, fibroblasts, and hepatocytes shift from CXCL12-dominant signaling toward CXCL1, CCL7, CCL6, and CCL4 signals. The young-enriched Neu01-TNFα subset preferentially engaged the CXCL12–CXCR4 axis, whereas the age-expanded Neu05 and Neu06 subsets were associated with CXCL1–CXCR2, providing a plausible chemotactic mechanism for the tissue-specific infiltration patterns.

The Neu06-IL6 state emerged as a central character. Pseudotime analysis placed these cells at the distal end of an inferred trajectory, with aged mice showing extended trajectory length and enrichment of Neu06 cells along the late path. The transcription factor CEBPB, which drives emergency granulopoiesis, and STAT3, the canonical IL-6 downstream effector, both increased along the aged ordering. In vitro, recombinant IL-6 activated STAT3 and raised reactive oxygen species production in HL-60 neutrophil-like cells, and conditioned medium from IL-6-stimulated cells induced senescence and matrix-remodeling markers in vascular smooth muscle and liver cell lines—an effect that persisted even after IL-6 washout, implying that IL-6-primed neutrophils release additional factors that propagate the signal.

The study also looked upstream, to the bone marrow. Single-cell analysis of hematopoietic progenitors revealed an aged-enriched state, HPC11, characterized by myeloid-biased genes such as Gata2, Car2, and Prtn3, in contrast to the lymphoid-primed HPC5 state enriched in young mice. Computational perturbation analysis predicted that FGF2 and angiopoietin-like 4 signaling shape the HPC11 program, consistent with the well-known myeloid skewing of aging hematopoiesis and providing a potential source for the flood of atypical neutrophils observed in peripheral tissues.

The authors are careful about causality. Their in vivo findings remain primarily associative, and the term aging-associated neutrophils refers to states enriched in aged organisms rather than neutrophils undergoing canonical senescence. Computational ligand–receptor and regulatory-network inferences are explicitly hypothesis-generating. Still, the partial conservation of these transcriptional programs in human multi-organ data from the Tabula Sapiens atlas, where older donors showed higher proportions of inflammatory and stress-responsive neutrophil states, lends weight to the framework. If future depletion, adoptive-transfer, or IL-6 blockade experiments confirm that these cells actively drive tissue decline, neutrophils may graduate from immune foot soldiers to prime suspects in the biology of aging—and targets for interventions aimed at slowing it.

Subject of Research: Aging-associated neutrophil remodeling across multiple mouse organs identified by single-cell transcriptomics

Article Title: Single‐Cell Mapping Identifies Aging‐Associated Neutrophil Remodeling Across Multiple Organs

Article References: Wang, Y., Chang, T., Fu, Y., Liang, G., Liu, H., Zhang, L., Yan, J., Liu, M., Liu, A., & Zhang, C. (2026). Single‐Cell Mapping Identifies Aging‐Associated Neutrophil Remodeling Across Multiple Organs. Aging Cell, 25(10), Article e70735. https://doi.org/10.1111/acel.70735

Image Credits: AI Generated

DOI: 10.1111/acel.70735

Keywords: neutrophils, aging, single-cell RNA sequencing, IL-6, senescence, bone marrow, granulopoiesis, inflammation, NETs, chemokines, STAT3, geromedicine

The scale of neutrophil involvement in cancer is staggering. Neutrophils are the most numerous circulating leukocytes in humans, produced at a rate of roughly one hundred billion cells per day in the bone marrow, and they can constitute the dominant immune population within many solid tumors. Large-scale analyses of the tumor immune landscape across human cancers have repeatedly found that high intratumoral neutrophil content correlates with poor prognosis in numerous malignancies, including renal cell carcinoma, head and neck cancer and non-small cell lung cancer. The neutrophil-to-lymphocyte ratio, a simple blood measurement, has emerged as one of the most robust prognostic biomarkers in oncology, predicting outcomes across tumor types and even forecasting response to immune checkpoint inhibitors.

Why would the immune system’s first responders become cancer’s accomplices? The answer, the review argues, lies in the extraordinary plasticity of neutrophils and their exquisite sensitivity to environmental cues. Tumors are, in the words of a classic 1986 observation by Harold Dvorak, wounds that do not heal, and neutrophils are the cells that respond to wounds. Cancers exploit the same inflammatory programs that neutrophils deploy during tissue repair. Tumor-derived signals such as granulocyte colony-stimulating factor, transforming growth factor-beta, interleukin-8 and other chemokines reprogram both the production and the function of neutrophils, driving emergency granulopoiesis in the bone marrow and recruiting immature, immunosuppressive granulocytes into the circulation and the tumor bed.

Once inside the tumor microenvironment, neutrophils promote cancer through several mechanistically distinct pathways. They release vascular endothelial growth factor and, critically, matrix metalloproteinase-9, an enzyme that liberates sequestered VEGF from the extracellular matrix and triggers the angiogenic switch that transforms a dormant lesion into a growing tumor. Studies in mouse models of multistage carcinogenesis showed that infiltrating neutrophils mediate this initial angiogenic switch, and human neutrophils are unique in releasing MMP-9 free of its natural inhibitor TIMP-1, making it an especially potent driver of new blood vessel formation. Neutrophil elastase, another granule protease, can degrade insulin receptor substrate-1 in tumor cells to accelerate lung tumor growth, and myeloid cell-derived reactive oxygen species have been shown to induce mutagenesis in adjacent epithelial cells, directly fueling the genomic instability that drives malignant transformation.

Perhaps no neutrophil behavior has attracted more attention in recent years than the formation of neutrophil extracellular traps, or NETs. First described in 2004 as web-like structures of DNA, histones and granule proteins that ensnare bacteria, NETs have since been implicated in a remarkable range of tumor-promoting processes. Recent work published in Nature demonstrated that NETs drive vascular occlusion, tumor necrosis and metastasis, linking phenomena long thought to be independent. NETs can sequester circulating tumor cells, shielding them from cytotoxic lymphocytes and natural killer cells; NET-associated DNA can bind the receptor CCDC25 on cancer cells, directing their migration; and NETs produced during systemic inflammation can awaken dormant cancer cells, triggering metastatic relapse years after primary tumor removal. Strikingly, the metastatic spread of breast cancer has been shown to accelerate during sleep, when rhythmic fluctuations in circulating neutrophils and cancer cell dynamics converge.

Neutrophils also construct the pre-metastatic niche, the distant soil that primary tumors prepare to receive their disseminated seeds. Tumor-derived factors mobilize neutrophils and their progenitors to future metastatic sites, where they suppress natural killer cell activity, remodel the extracellular matrix and create an immunologically permissive environment. In breast cancer models, neutrophils support the lung colonization of metastasis-initiating cells, and chronic stress has been shown to increase metastasis through neutrophil-mediated changes to the microenvironment. Even glucocorticoids, widely used clinically, can promote breast cancer metastasis by acting on these cells. The circadian biology of neutrophils, governed by an intrinsic molecular timer that coordinates immune defense and vascular protection, adds another layer of complexity to how and when these cells enable metastatic spread.

Yet the story is emphatically not one-directional. The review devotes substantial attention to the antitumor capacities of neutrophils, which many of the same molecules can mediate depending on context. Neutrophil elastase, which promotes tumor growth in some settings, has been shown in other contexts to selectively kill cancer cells and attenuate tumorigenesis, with important differences between mouse and human neutrophils in the production of its inhibitor, secretory leukocyte proteinase inhibitor. Activated neutrophils exert direct cytotoxicity against melanoma cells through reactive oxygen species, and tumor-associated neutrophils in early-stage human lung cancer can stimulate T cell responses rather than suppress them. Tumor-entrained neutrophils have even been shown to inhibit metastatic seeding in the lung, providing early evidence of spontaneous antimetastatic function. The pro- versus antitumor polarization of neutrophils, famously framed as N1 versus N2 states, is now understood to reflect a continuum of environmentally determined functional states rather than fixed identities.

This dual nature is precisely what makes neutrophils such compelling therapeutic targets. The review highlights several promising strategies. Neutrophil-activating therapy, developed by the Stanford group, demonstrated that pharmacologically activated neutrophils can eradicate tumors and reduce metastases independently of adaptive immunity. CD40 agonist antibodies recruit a subset of neutrophils associated with tumor control, and T cell immunotherapies have been shown to engage neutrophils to eliminate antigen-escape variants that would otherwise survive checkpoint blockade. Bacille Calmette-Guerin, the century-old tuberculosis vaccine used to treat bladder cancer, works in part by reprogramming hematopoiesis so that neutrophils develop the capacity to attack tumor cells, and interferon-gamma induces NET formation with tumor-killing activity in colorectal cancer. On the inhibitory side, CXCR2 antagonists, peptidyl arginine deiminase 4 inhibitors that block NET formation, arginase inhibitors, and antibodies that block the NET-associated immunosuppressive enzyme arginase-1 are all in clinical development, several in combination with checkpoint inhibitors.

Antibody-based approaches represent another frontier. Neutrophils are extraordinarily potent mediators of antibody-dependent cellular cytotoxicity, and IgA antibodies in particular trigger superior neutrophil-mediated killing of cancer cells compared with conventional IgG, engaging the Fc-alpha receptor to produce vigorous respiratory bursts and trogoptosis, a process in which neutrophils progressively strip membrane fragments from antibody-coated targets. Combining IgA-based therapeutics with blockade of the CD47-SIRP-alpha innate immune checkpoint, which prevents phagocytosis, has shown enhanced neutrophil cytotoxicity against neuroblastoma and other malignancies. Even more ambitiously, researchers have engineered chimeric antigen receptor neutrophils derived from induced pluripotent stem cells, which possess potent activity against solid tumors and can serve as delivery vehicles for tumor-microenvironment-responsive nanodrugs in glioblastoma. Neutrophils bearing adhesive polymer micropatches have been proposed as a drug-free immunotherapy platform.

The authors caution that translating these findings into the clinic requires resolving fundamental questions about neutrophil heterogeneity, nomenclature and species differences. A consensus statement has established standards for myeloid-derived suppressor cell classification, and recent single-cell atlases have mapped neutrophil developmental trajectories across tissues and disease states, revealing that mature and immature neutrophils converge on similar transcriptional signatures within tumors. Human and mouse neutrophils differ in important ways, including their circadian rhythms, granule composition and lifespan, with human neutrophils surviving approximately five days rather than hours as once believed. Nevertheless, the convergence of mechanistic insight, biomarker validation and early clinical activity suggests that the field has reached an inflection point. Neutrophils, long dismissed as terminally differentiated foot soldiers, are now recognized as master regulators of the tumor ecosystem, and learning to command them, rather than simply deplete them, may define the next era of cancer immunotherapy.

Subject of Research: The roles of neutrophils in tumor progression, immunosuppression, metastasis and cancer therapy

Article Title: Neutrophils in cancer

Article References: Diehl, M. I., Basto, P. A., Abikenari, M. A., Linde, I. L., Okwan-Duodu, D., & Engleman, E. G. (2026). Neutrophils in cancer. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00968-2

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00968-2

Keywords: neutrophils, cancer, tumor microenvironment, neutrophil extracellular traps, metastasis, immunosuppression, angiogenesis, tumor-associated neutrophils, immunotherapy, myeloid-derived suppressor cells, NETosis, granulopoiesis