Immunotherapy has revolutionized cancer treatment by leveraging the patient’s own immune system to attack malignant cells. Despite its promise, the success of immunotherapies in solid tumors like non-small cell lung cancer (NSCLC) remains limited. A significant hurdle is the infiltration of pro-tumoral macrophages—immune cells that instead of combating cancer, help suppress the antitumor immune response. These macrophages create an immunosuppressive microenvironment, aiding tumor growth and survival. Prior assumptions held that such macrophages adopted their pro-cancer roles only after arriving at the tumor. The new findings overturn this idea by tracing the origin of this immune subversion back to the bone marrow, where macrophage precursors undergo critical changes.

Employing cutting-edge single-cell genomics and lineage-tracing technologies, the researchers mapped the developmental trajectory of bone marrow myeloid progenitor cells, the precursors to macrophages. Their analyses uncovered that tumors broadcast signals that deliver a “first hit” to these progenitor cells in the bone marrow. This initial exposure biases the developing immune cells toward an immunosuppressive phenotype even before they infiltrate the tumor. Later, once in the tumor microenvironment, a “second hit” acts as a catalyst that locks these macrophages into their pro-tumoral functions. This two-step model represents a paradigm shift in our understanding of immune cell education by cancer.

Dr. Samarth Hegde, the study’s lead author, highlights that the temporal aspect of immune suppression had been misunderstood for decades. Observing that immune cells are preconditioned within the bone marrow demands a radical rethink of therapeutic strategies. Traditional approaches focus predominantly on the tumor microenvironment, attempting to re-educate or inhibit macrophages after they have already entrenched themselves among cancer cells. This study suggests that such attempts might be inherently limited. Targeting the progenitor cells prior to their arrival at the tumor could prevent them from becoming immunosuppressive in the first place, thus preserving the immune system’s capacity to mount effective anticancer responses.

One of the most promising molecular candidates identified in this reprogramming process is NRF2, a transcription factor fundamentally involved in cellular stress responses and redox homeostasis. The research team discovered that NRF2 activity is modulated in bone marrow progenitor cells exposed to tumor-derived inflammatory signals, rewiring these cells’ genetic programs. This NRF2-driven reprogramming becomes fully operational when the progenitors differentiate into tumor-infiltrating macrophages, promoting immune suppression and tumor progression in both human patients and mouse models. Crucially, inhibiting NRF2—either through genetic manipulation or experimental pharmacological agents—significantly reduced the formation of suppressive macrophages and revitalized antitumor immunity in preclinical experiments.

Miriam Merad, MD, PhD, senior corresponding author and Chair of Immunology and Immunotherapy at Mount Sinai, emphasizes the translational potential of these findings. By targeting NRF2 signaling in bone marrow progenitors, it might be possible to halt the supply line of immunosuppressive macrophages at its source, essentially cutting off the tumor’s capacity to subvert the immune system. “Current immunotherapies largely address the tumor itself but fail to consider the precursor immune cells’ prior ‘education,’” Dr. Merad notes. “Early intervention at the progenitor stage could dramatically improve the durability of treatment responses and possibly reduce relapse rates.”

Additionally, this newly revealed mechanism of immune cell manipulation by tumors offers a compelling opportunity for diagnostic innovation. Since the reprogrammed myeloid progenitors circulate in the bloodstream before differentiating, blood-based tests could detect these “pre-programmed” immune cells, facilitating earlier diagnosis and enabling timely therapeutic intervention. Such liquid biopsies would mark a significant advance in personalized medicine, allowing clinicians to monitor immune cell states during treatment and remission with unprecedented precision.

The implications of this research extend well beyond lung cancer. The investigators plan to explore whether similar genetic and epigenetic mechanisms govern immune cell progenitor reprogramming in other malignancies and chronic inflammatory diseases such as aging, obesity, and atherosclerosis. These conditions often share dysregulated immune responses, and understanding the underlying molecular controls, including NRF2 signaling, may reveal new treatment opportunities. Moreover, aberrant immune cell proliferation outside of the bone marrow—called extramedullary hematopoiesis—is observed in some cancers, and the team aims to investigate if comparable molecular programs are at play there as well.

A critical future direction involves elucidating how NRF2 and related pathways influence the metabolic reprogramming of immune cells. Tumors are known to manipulate cellular metabolism to evade immunity, and dissecting these interactions at the molecular level may clarify how suppressive macrophages gain their functional phenotype. This could lead to novel metabolic interventions that complement existing immunotherapies, creating multi-pronged strategies to outsmart cancer.

The publication titled “Myeloid Progenitor dysregulation fuels immunosuppressive macrophages in tumors” represents a landmark achievement in cancer immunology. By highlighting how tumors manipulate immune cells from their earliest developmental stages, it provides a blueprint for the next generation of cancer therapies focused on the immune system’s origins rather than its endpoints. This foundational work not only advances scientific understanding but also heralds a promising translational leap toward more effective and durable treatment regimens for patients battling lung cancer and potentially other challenging diseases.

This discovery underscores the critical role of interdisciplinary collaboration and advanced technologies in unraveling the complexity of cancer biology. The team’s integration of genomics, immunology, and translational medicine exemplifies the frontier of precision immunology research, making Mount Sinai a leader in tackling the most stubborn challenges in oncology.

Subject of Research: Cells
Article Title: Myeloid Progenitor dysregulation fuels immunosuppressive macrophages in tumors
News Publication Date: 10-Sep-2025
Web References: https://www.nature.com/articles/s41586-025-09493-y
References: DOI 10.1038/s41586-025-09493-y
Keywords: Cancer immunotherapy

The innovative WTS assay developed by Zhao et al. offers a highly sensitive and specific platform that captures not only gene fusions but also critical RNA alterations like MET exon 14 skipping and EGFR VIII mutations, broadening its clinical utility. By leveraging whole transcriptome sequencing rather than targeted panels, this assay examines the entirety of RNA transcripts, thus enabling an unbiased exploration of fusion events across the transcriptome. This holistic approach allows clinicians and researchers to uncover both known and novel fusion transcripts that may impact diagnosis, prognosis, or targeted therapy options.

A significant hurdle in transcriptome analysis is RNA quality. RNA degradation can severely impair sequencing outcomes and fusion detection. To overcome this, the team identified a key quality metric—DV200—representing the percentage of RNA fragments longer than 200 nucleotides. They established a threshold of DV200 ≥ 30% to ensure sufficient RNA integrity for accurate fusion calling. This parameter provides a practical cut-off for clinical laboratories to assess sample suitability and enhance assay performance, addressing one of the major technical barriers in RNA sequencing from clinical specimens.

Optimization of input RNA quantity and sequencing depth were also focal points in the assay development. The researchers determined that using at least 100 ng of RNA input, combined with a minimum of 80 million mapped reads per sample, maximized the assay’s sensitivity. Additionally, they defined expression thresholds—specifically, fusion transcript levels exceeding 40 copies per nanogram of input RNA—necessary to confidently identify fusion events. These performance benchmarks not only improve detection rates but also help standardize protocols for routine clinical application.

The validation phase of this WTS assay demonstrated robust clinical utility. Out of 63 previously characterized gene fusion-positive samples, the assay correctly identified 62, yielding an impressive sensitivity of 98.4%. Equally important, the assay exhibited 100% specificity by reporting no fusions in 21 known fusion-negative control samples. This combination of high sensitivity and specificity underscores its potential as a reliable diagnostic tool that minimizes both false positives and false negatives, a critical balance in precision oncology.

Reproducibility and repeatability are crucial for any diagnostic assay, particularly in clinical settings where consistency impacts patient outcomes. The research team conducted rigorous repeat testing on multiple samples and observed excellent concordance, affirming the assay’s robustness. An exception was noted with the TPM3::NTRK1 fusion, which was expressed at levels below the established threshold, highlighting ongoing challenges in detecting ultra-low abundance fusions. Nonetheless, these findings suggest that the assay can be confidently implemented for a broad range of fusion detection scenarios.

One of the most striking aspects of this study is the application of the WTS assay to real-world clinical samples from patients with non-small cell lung cancer (NSCLC). Among these samples, 68.9% of identified fusions were classified as potentially actionable, meaning they could guide targeted therapy decisions. This is in contrast to a 20% actionable fusion rate observed in a wider pan-cancer cohort, illustrating the assay’s value in stratifying patients for personalized treatment based on fusion profile.

Beyond actionable fusions, the assay also uncovered numerous gene fusions with potential diagnostic and prognostic significance across various tumor types. These findings expand the understanding of the fusion landscape in oncology and open avenues for further research into novel biomarkers. The ability to systematically profile such fusions across different cancers underscores the versatility and comprehensive capacity of whole transcriptome sequencing.

Technically, the WTS assay employs advanced sequencing technologies coupled with refined bioinformatics pipelines. This integration enables the high-throughput identification of fusion events alongside MET exon 14 skipping and EGFR VIII alterations, which have known clinical implications. The multiplexed detection capability allows simultaneous assessment of multiple RNA abnormalities, thereby streamlining molecular diagnostics into a single, cohesive workflow.

Moreover, by circumventing the limitations of targeted sequencing panels, which test predefined fusion partners, this assay can detect rare or atypical fusion events that may otherwise be missed. This advantage is particularly important in heterogeneous tumors or in cases where emerging or novel fusions could inform therapeutic strategies. The open-ended nature of whole transcriptome sequencing thus sets a new standard for exploratory and diagnostic cancer genomics.

The study also emphasizes the importance of quality control metrics and standardized thresholds in facilitating the translation of WTS from research to clinical use. Parameters like RNA input, DV200 value, and minimal read counts form the backbone of assay reliability, enabling consistent results across laboratories. This technical rigor ensures that the assay’s promising sensitivity and specificity are reproducible in diverse clinical environments.

Importantly, the high sensitivity of the assay not only improves detection rates but also allows for the identification of low-abundance fusions, which could have been overlooked by less comprehensive methods. This sensitivity has significant implications for early diagnosis and monitoring of residual disease, where fusion transcript levels may be minimal yet clinically important.

Looking ahead, the integration of such WTS assays into routine clinical workflows holds promise for transforming cancer care. The ability to capture the full fusion transcriptome in a single test accelerates molecular diagnostics and offers a more complete molecular profile to oncologists. This comprehensive approach supports precision medicine by identifying patients eligible for fusion-targeted therapies, novel clinical trials, or those requiring specialized monitoring.

Furthermore, the inclusion of fusion events with diagnostic and prognostic relevance enriches the molecular characterization of tumors. This may lead to improved risk stratification and treatment personalization, ultimately enhancing patient outcomes. As cancer treatment paradigms increasingly rely on molecularly driven decisions, assays like the one developed here will be instrumental in pushing the boundaries of precision oncology.

In summary, the work by Zhao and colleagues represents a significant advance in cancer genomics. Their novel WTS assay provides a sensitive, specific, and reproducible method for detecting gene fusions and related RNA alterations in clinical cancer specimens. By enabling comprehensive fusion profiling across tumor types, this assay sets a new benchmark for molecular diagnostics and reinforces the transformative potential of whole transcriptome sequencing in oncology.

The implications of this research extend beyond technical development; they embody an important step towards personalized cancer care, where every patient’s tumor transcriptome is utilized to guide optimal therapy. Continued validation and adoption of such assays will likely fuel further discoveries in fusion biology and expand the catalog of actionable alterations accessible through next-generation sequencing technologies.

As precision oncology evolves, tools that combine thorough molecular characterization with clinical applicability will shape the future of cancer diagnosis and treatment. Zhao et al.’s whole transcriptome sequencing assay exemplifies this paradigm, offering a powerful resource for uncovering the complexities of gene fusions and enhancing the therapeutic landscape for cancer patients worldwide.

Subject of Research: Development of a whole transcriptome sequencing assay for detection of gene fusions and related RNA alterations in clinical cancer samples.

Article Title: Development and application of a whole transcriptome sequencing assay for the detection of gene fusions in clinical cancer specimens.

Article References:
Zhao, S., Du, X., Zhang, Y. et al. Development and application of a whole transcriptome sequencing assay for the detection of gene fusions in clinical cancer specimens. BMC Cancer 25, 842 (2025). https://doi.org/10.1186/s12885-025-14186-w

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14186-w

Among the many pathways implicated in breast cancer, the PI3K/Akt/mTOR pathway has garnered considerable attention. It serves as a central conduit for growth signals, especially in hormone receptor-positive and HER2-positive breast cancer subtypes. Hyperactivation of this pathway can occur due to various mutations, including alterations in the PIK3CA gene and the loss of the tumor suppressor PTEN. These molecular changes not only drive cancer progression but also contribute to therapeutic resistance, complicating treatment outcomes and necessitating innovative approaches for targeted intervention.

Another noteworthy pathway highlighted in the review is RAS/RAF/MEK/ERK, which is crucial for controlling cell proliferation and survival. Even in the absence of classical mutations, this pathway can become activated under specific conditions, particularly when primary growth signals are obstructed. This phenomenon has been observed in HER2-positive and triple-negative breast cancer cases, where the reliance on alternative pathways becomes evident. Understanding the nuances of these signaling interactions opens avenues for novel therapeutic modalities that can address these challenges directly.

The role of the Wnt/β-catenin signaling pathway is also crucial in breast cancer biology, particularly concerning its involvement in processes such as epithelial-mesenchymal transition (EMT) and metastasis. Activation of this pathway can potentiate the invasive properties of cancer cells, thus enhancing their ability to spread beyond the primary tumor site. Researchers continue to investigate ways to inhibit Wnt signaling to curb metastasis, highlighting a burgeoning avenue for future cancer therapeutics.

The Notch signaling pathway has gained attention for its dual role in development and tumorigenesis. Its activation in breast cancer is implicated in promoting self-renewal of cancer stem cells and driving tumor progression. Exploring targeted therapies that can modulate Notch signaling may provide strategies to not only inhibit tumor growth but also effectively tackle recurrence and resistance, addressing a critical aspect of cancer treatment.

Similarly, the NF-κB signaling pathway is integral to regulating inflammation and immune responses in both normal physiology and cancer. Dysregulation of NF-κB in breast cancer has been linked to enhanced cell survival, further complicating therapeutic efforts. By understanding the mechanisms through which NF-κB contributes to oncogenic processes, researchers can develop innovative strategies to manipulate this pathway, potentially reversing its pro-cancerous effects.

In addition to the aforementioned pathways, the DNA damage response (DDR) pathway plays a pivotal role in maintaining genomic integrity. The review underscores how dysregulation of DDR pathways—often due to mutations in genes like BRCA1 and BRCA2—leads to compromised DNA repair mechanisms, resulting in genomic instability. This aspect of breast cancer biology highlights the potential for targeted therapies that could exploit vulnerabilities in the DDR machinery, offering new therapeutic avenues for treatment-resistant tumors.

The implications of these signaling abnormalities extend beyond understanding cancer biology; they influence the design and efficacy of treatment regimes. With many therapies currently in clinical trials targeting these critical pathways, there is hope that we may soon see healthcare professionals equipped with nuanced, molecule-specific strategies that enhance patient outcomes. Combining modalities that target multiple pathways may yield synergistic effects, ultimately leading to improved therapeutic efficacy and reduced risk of resistance.

Researchers emphasize the importance of personalized medicine in the context of breast cancer treatment. By tailoring therapies to the unique genetic alterations present in individual tumors, oncologists can optimize treatment efficacy while minimizing potential side effects. Such personalized approaches promise to revolutionize breast cancer care, offering hope to patients confronting advanced and treatment-resistant forms of the disease.

The growing understanding of the interplay between various signaling pathways in breast cancer underscores the need for continued research and investment in this field. The pursuit of innovative therapies that target these pathways will be critical as we strive to improve survival rates and quality of life for breast cancer patients. As the scientific community collaborates toward a common goal of unearthing the complexities of tumor biology, we edge closer to a future where breast cancer is not only treatable but manageable.

In conclusion, the critical examination of signaling pathway dysregulation in breast cancer marks a vital step in our journey toward personalized medicine. With researchers like Dinara Ryspayeva and her colleagues at Brown University leading the charge, the prospects for improved therapeutic strategies become increasingly tangible. As we harness these insights, it is our responsibility to advocate for continued funding and support for research initiatives that prioritize patient-centric outcomes in cancer care.

Subject of Research:
Article Title: Signaling pathway dysregulation in breast cancer
News Publication Date: March 25, 2025
Web References: Oncotarget
References:
Image Credits: © 2025 Ryspayeva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0)
Keywords: breast cancer, signaling pathways, oncogenic mechanisms, personalized medicine, therapeutic strategies, clinical trials.