In the relentless battle against cancer, one of the most formidable challenges remains bone metastases—the spreading of malignant cells to the bone, a complication often seen in advanced stages of lung, breast, and prostate cancers. These bone metastases not only cause significant morbidity but also demonstrate a troubling resistance to conventional therapies, including the revolutionary immunotherapies that have transformed the treatment landscape for many other tumor types. A groundbreaking study from Ludwig Cancer Research, spearheaded by Taha Merghoub and Tao Shi of the Ludwig Collaborative Laboratory at Weill Cornell Medicine, in collaboration with experts from Nanjing University, has now unraveled a critical mechanism underpinning this immune resistance in bone metastases.
Central to their discovery is the identification of a complex reprogramming of neutrophils—white blood cells that serve as primary responders in the innate immune system—within the tumor microenvironment of bone metastases. Unlike their typical mature counterparts that aid in attacking tumors, these neutrophils are converted into an immature, immunosuppressive state. This altered functional phenotype, the researchers report in the exacting pages of Cancer Cell, severely blunts the anti-tumor immune response. The culprit behind this neutrophil reprogramming is a protein called Dickkopf-related protein 1 (DKK1), which is abundantly produced by the bone tumor niche.
DKK1, previously implicated in bone biology and cancer progression, acts as a molecular architect that remodels the cellular landscape to favor tumor persistence. Through a sophisticated series of biochemical signals, DKK1 disrupts neutrophil maturation, which consequently fosters a tumor-friendly microenvironment. This aberrant state is marked by the production of another molecule, chitinase 3-like 3 (CHI3L3), which exerts potent suppressive effects on cytotoxic CD8+ T cells—the main warriors of the adaptive immune system tasked with identifying and destroying malignant cells.
Previous research has shown neutrophils to be ambivalent players in cancer biology, with their role oscillating between tumor promotion and tumor suppression depending on their specific activation states. The Merghoub and Shi study crucially emphasizes that it is the immature, DKK1-reprogrammed neutrophils that dominate within bone metastases, effectively erecting an immunological shield that thwarts therapies designed to unleash T cell-mediated killing. This insight elucidates a pivotal reason why immune checkpoint blockade therapies, such as anti-PD-1 antibodies, fail to produce significant responses in patients whose cancers have metastasized to the bone.
In meticulously designed mouse models of triple-negative breast cancer metastatic to bone, the researchers demonstrated that blocking DKK1 with a targeted antibody markedly reversed this immune suppression. This intervention allowed neutrophils to mature appropriately, reducing CHI3L3 levels and relieving the inhibition on CD8+ T cells. Remarkably, when DKK1 blockade was combined with immune checkpoint inhibitors, tumors regressed dramatically, with some completely eradicated. These findings provide compelling preclinical evidence that DKK1-targeted therapies could synergize with existing immunotherapies to overcome resistance in bone metastases, a dire unmet clinical need.
Expanding beyond preclinical models, their analyses included patient-derived serum samples from individuals with gastric cancer and bone metastases, where elevated DKK1 levels mirrored those observed in experimental contexts. This translational aspect not only reinforces the relevance of their findings to human disease but also suggests potential biomarkers—DKK1 and CHI3L3—that could stratify patients likely to benefit from combined immunotherapeutic approaches targeting both neutrophils and T cells.
From a mechanistic standpoint, the study delved deep into the intracellular signaling pathways activated by DKK1 that orchestrate neutrophil dysfunction. By pinpointing these molecular conduits, the research identifies multiple potential pharmacological targets beyond DKK1 itself, broadening the horizon for drug development aiming to recalibrate the immune microenvironment in metastatic bone lesions.
This research further challenges the established focus on targeting adaptive immunity alone, emphasizing the critical role of innate immune cells—particularly neutrophils—in shaping therapeutic outcomes. The data argue for an integrated immunotherapeutic strategy that not only reinvigorates T cells but simultaneously reprograms neutrophils away from a suppressive phenotype, thus unleashing a coordinated immune assault on cancer.
The clinical implications are especially promising, given that DKN-01, a DKK1-blocking antibody, is already in clinical trials, accelerating the potential translation of these discoveries into effective treatments. The identification of CHI3L3 and its gene expression signatures as biomarkers opens avenues for precision medicine, enabling oncologists to tailor therapies according to the immune landscape of individual tumors.
The broader significance of this study lies in its illumination of the complex interplay between cancer cells and their microenvironment, specifically within the unique immunosuppressive context of bone metastases. By unveiling the molecular and cellular underpinnings of immunotherapy resistance, this work not only advances our understanding of cancer biology but also offers a tangible path toward improving outcomes for patients grappling with metastatic disease, for whom therapeutic options remain woefully inadequate.
In summation, this rigorous investigation by Merghoub, Shi, and colleagues delineates a novel immunosuppressive axis driven by DKK1-induced neutrophil immaturity within bone metastases. Intervening in this axis restores immune competency, sensitizes tumors to checkpoint blockade, and presents a compelling target for next-generation cancer immunotherapies. Their findings herald a paradigm shift, advocating for the co-targeting of innate and adaptive immunity in combating metastatic cancer, with a profound potential to reshape clinical practice and patient survival.
Subject of Research: Neutrophil reprogramming and immunotherapy resistance in bone metastases mediated by DKK1.
Article Title: DKK1-mediated neutrophil reprogramming fosters immunotherapy resistance in bone metastases.
News Publication Date: August 7, 2025.
Web References:
- Cancer Cell article: https://www.sciencedirect.com/science/article/abs/pii/S1535610825003137?via%3Dihub
- Related neutrophil study: https://www.nature.com/articles/s41422-025-01145-0
Image Credits: Ludwig Cancer Research, image of Taha Merghoub.
Keywords: Health and medicine, Cancer, Immunotherapy, Neutrophils, Bone metastases, DKK1, Tumor microenvironment, CD8+ T cells, Innate immunity, Immune checkpoint blockade.
