Colorectal cancer remains a formidable challenge, ranking among the leading causes of cancer mortality worldwide. Despite advances in immunotherapy and targeted treatments, the tumor microenvironment continues to thwart effective immune responses. Central to this hostile microenvironment are CAFs, a heterogeneous population of stromal cells that foster immune evasion, promote tumor growth, and contribute to therapeutic refractory states. These fibroblasts secrete immunosuppressive cytokines and extracellular matrix components that not only physically shield cancer cells but also alter the immune landscape, creating a sanctuary for tumor survival.

Traditional approaches to dismantle this tumor stroma have met with limited success due to the complexity and plasticity of CAFs. However, the current research takes advantage of a novel cellular vulnerability—ferroptosis, an iron-dependent form of regulated cell death distinguished by lipid peroxidation. Unlike apoptosis or necrosis, ferroptosis triggers a lethal accumulation of oxidative damage to membrane lipids, offering a unique pathway to eradicate malignant and supportive cells that are otherwise resistant to cell death.

The innovative aspect of this study lies in harnessing nanotechnology to deliver ferroptosis inducers selectively to CAFs within the colorectal tumor microenvironment. By engineering nanocarriers that can navigate and penetrate the dense stromal architecture, the researchers ensured that the ferroptosis-inducing compounds reached their cellular targets effectively, minimizing off-target effects and systemic toxicity. This nano-enabled precision therapy epitomizes the convergence of molecular oncology and materials science, opening new therapeutic avenues that were previously inaccessible.

Mechanistically, the nanotherapy disrupts the metabolic and redox homeostasis in CAFs, precipitating an iron-catalyzed cascade of lipid peroxide accumulation. This not only induces ferroptotic cell death in the fibroblasts but also reverses the immunosuppressive landscape they maintain. The ablation of CAFs alleviates dense extracellular matrix deposition and diminishes inhibitory cytokines, thereby reawakening anti-tumor immune surveillance and enhancing the infiltration and activity of cytotoxic T cells within the tumor bed.

The study leverages advanced molecular profiling to characterize the phenotypic changes in CAFs following ferroptosis induction. Detailed transcriptomic and proteomic analyses reveal downregulation of key fibroblast activation markers and immunomodulatory factors, underscoring the efficacy of this approach in remodeling the tumor microenvironment. This comprehensive molecular insight is critical, as it confirms that the therapy does not merely kill CAFs but fundamentally reprograms the stromal niche towards an immune-permissive state.

Furthermore, preclinical models of colorectal cancer demonstrated remarkable therapeutic outcomes when treated with the ferroptosis-based nanotherapy. Tumor burden was significantly reduced, accompanied by prolonged survival and enhanced response to checkpoint blockade immunotherapies. These results indicate a promising synergistic potential, wherein the nanotherapy primes the tumor microenvironment to become more amenable to existing immunotherapeutic interventions, paving the way for combinatorial clinical strategies.

The safety profile of the nanotherapy was rigorously assessed, revealing minimal systemic toxicity and negligible adverse effects on normal tissue fibroblasts. This selectivity is attributed to the unique microenvironmental conditions within the cancerous stroma—such as elevated iron levels and oxidative stress—that sensitize CAFs to ferroptotic triggers. The targeted nature of this approach highlights its translational promise, potentially overcoming one of the major hurdles in stroma-directed cancer therapies: collateral damage to healthy tissue.

The implications of this research extend beyond colorectal cancer. Given the pervasive role of CAFs in various solid tumors, the principles of ferroptosis-induced stromal modulation could inspire broad applications across oncology. Tumors characterized by dense fibrotic stroma, including pancreatic and breast cancers, may particularly benefit from analogous nanotherapeutic strategies, transforming how clinicians confront tumor heterogeneity and microenvironmental resistance mechanisms.

Critically, this study also challenges the current paradigms of tumor biology and treatment. It compels the scientific community to reconsider the tumor microenvironment not merely as a passive scaffold but as an active determinant of cancer evolution and therapy resistance. Therapeutic designs that integrate stroma-targeting with immune modulation, as exemplified by this ferroptosis nanotherapy, underscore a new era of precision oncology tailored to dismantle the multifaceted tumor ecosystem.

Ongoing research aims to optimize the nanocarrier design further, enhancing targeting efficiency and payload stability, while clinical translation efforts are being initiated to evaluate safety and efficacy in human patients. The interdisciplinary collaboration between oncologists, nanotechnologists, and immunologists exemplified by this accomplishment illustrates the dynamic integration of diverse scientific domains necessary to conquer cancer’s complexities.

In sum, the ferroptosis-based nanotherapy developed by Wang and colleagues marks a transformative leap in colorectal cancer treatment, illuminating a path where manipulating the tumor microenvironment via regulated cell death pathways can synergize with immune activation. This pioneering work enriches the arsenal against colorectal cancer and renews hope for durable therapeutic responses in malignancies historically resistant to conventional interventions.

Subject of Research: Colorectal cancer tumor microenvironment and stromal modulation by ferroptosis-based nanotherapy.

Article Title: Amelioration of colorectal cancer-associated fibroblasts in immunosuppressive microenvironment by ferroptosis-based nanotherapy.

Article References: Wang, S., Wang, Z., Wu, C. et al. Amelioration of colorectal cancer-associated fibroblasts in immunosuppressive microenvironment by ferroptosis-based nanotherapy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69462-5

Image Credits: AI Generated

One of the pivotal revelations centers on the enigmatic influence of bacteria residing within tumors, which has long eluded comprehensive scientific understanding. The research team discovered a novel biological mechanism illustrating how these intratumoral microorganisms actively contribute to therapeutic resistance in oral and colorectal cancers. By evading the immune system’s surveillance and undermining chemotherapy efficacy, these bacteria essentially enable tumors to fortify themselves against conventional treatments. This finding opens a new frontier in oncology, highlighting a microbial dimension of tumor biology previously invisible to researchers. Dr. Susan Bullman, an associate professor of Immunology and a key investigator, emphasizes the transformative potential of this insight, suggesting that it could underpin the development of “microbe-aware” cancer therapies designed to dismantle these protective bacterial influences.

Expanding the immunological frontier, another study identifies a potent biomarker predictive of enhanced immunotherapy responses in solid tumors. The researchers implicated mutations in the TET2 gene as fundamental in priming certain white blood cells, thereby augmenting antigen presentation and invigorating T cell activation. This enhanced immune recognition amplifies the therapeutic potency of checkpoint inhibitors and other immunomodulatory treatments. Validated across extensive datasets encompassing nearly 60,000 patients, this discovery underscores the molecular interplay dictating treatment success and lays the groundwork for more personalized immunotherapy regimens. Dr. Padmanee Sharma, a leading immunologist at MD Anderson, describes this breakthrough as a key to “unlocking complex relationships in solid tumor immunology,” heralding a new era of precision medicine.

The challenge of optimizing care at the end of life for cancer patients remains at the forefront of oncological ethics and clinical practice. A comprehensive study assessed the impacts of administering systemic anti-cancer therapy to patients in their final 30 days of life. The data revealed a correlational increase in hospitalizations, emergency department visits, and intensive care unit admissions, alongside a marked decrease in hospice utilization. This pattern suggests that aggressive treatment strategies may inadvertently undermine quality of life, imposing burdensome interventions during a vulnerable period. Dr. Kerin Adelson, MD Anderson’s chief quality and value officer, advocates for a reevaluation of therapeutic approaches, emphasizing the need to balance life-extending efforts with palliative care to mitigate unnecessary medicalization and honor patient dignity.

On the technological vanguard, researchers introduced Comparing and Contrasting Spatial Transcriptomics (CoCo-ST), a sophisticated computational methodology enhancing the resolution of spatial transcriptomic data. This innovative technique provides unprecedented clarity in detecting precancerous tissue alterations at a microscopic scale, previously masked by standard analytic limitations. By refining the spatial context of gene expression patterns within tissue sections, CoCo-ST enables scientists to map early carcinogenic transformations, offering critical insights into tumorigenesis. Dr. Jia Wu, an expert in Imaging Physics, underscores the importance of this tool in illuminating the subtle, initial deviations that precipitate cancer, thereby facilitating earlier diagnosis and intervention strategies.

In the domain of hematologic malignancies, a study examining hematopoietic cell transplantation (HCT) outcomes in adolescents and young adults with acute lymphoblastic leukemia (ALL) has yielded encouraging results. Focused on patients achieving a second remission, the data demonstrate that HCT can serve as a curative modality when integrated with assessments of minimal residual disease and overall patient health. This nuanced approach enables personalized treatment planning, optimizing survival prospects while minimizing relapse risks. Dr. Partow Kebriaei articulates the promise of stem cell transplantation in offering “real hope” for this demographic, highlighting the import of tailored interventions grounded in molecular and clinical metrics.

Complementing these clinical advances, an investigation into neuronal differentiation has spotlighted the epigenetic regulator KMT2D, a protein frequently mutated in medulloblastoma. The study elucidates KMT2D’s critical role in orchestrating gene expression programs essential for the development of neurons implicated in motor coordination and cognitive function. These findings bridge the gap between cancer epigenetics and neurodevelopmental biology, revealing that disruptions in KMT2D-mediated pathways may underlie both oncogenic processes and neurological deficits. Dr. Min Gyu Lee remarks on the significance of uncovering the epigenetic mechanisms governed by KMT2D as foundational to understanding medulloblastoma pathogenesis.

Moreover, the field of immunotherapy benefits from nuanced insights into genetic determinants shaping patient responses to chimeric antigen receptor (CAR) T cell therapy in large B-cell lymphoma (LBCL). Researchers identified multiple genetic markers influencing treatment efficacy, furnishing critical criteria for stratifying patient candidacy. By delineating these genetic predictors, clinicians can better tailor immunotherapeutic approaches, enhancing response rates and long-term remission. Dr. Paolo Strati underscores the translational impact of this work, which paves the way for refined patient selection and strategic interventions to potentiate CAR T cell function in refractory lymphomas.

These scientific milestones have garnered widespread recognition, with Dr. Susan Bullman named among TIME’s prestigious 2025 TIME100 Next for her pioneering contributions. Additionally, Dr. Jeffrey Gershenwald was elected Chair of the American Joint Committee on Cancer, underscoring MD Anderson’s leadership role in shaping oncological standards. Faculty achievements extend into interprofessional realms as well, exemplified by Kimberly Hoggatt Krumwiede’s fellowship selection by the Association of Schools Advancing Health Professions and Dr. Carin Hagberg’s receipt of the Excellence in Education Award from the American Society of Anesthesiologists.

Collectively, these findings not only propel the scientific understanding of cancer biology but also carve pathways toward more efficacious, patient-centric therapies. By integrating microbial ecology, immunogenetics, computational precision, and clinical pragmatism, MD Anderson researchers are reshaping the contours of cancer care. Their work heralds a future where personalized medicine transcends conventional barriers, offering hope through innovation to patients confronting the formidable challenge of cancer.

Subject of Research: Cancer biology, immunotherapy, tumor microbiome, computational biology, hematopoietic cell transplantation, neuronal differentiation, genetic markers in lymphoma therapy

Article Title: Breakthroughs in Cancer Resistance, Immunotherapy Biomarkers, and Early Detection Unveiled by MD Anderson Researchers

News Publication Date: October 16, 2025

Web References:

• Study on bacteria driving treatment resistance: https://www.mdanderson.org/newsroom/research-newsroom/study-reveals-how-bacteria-in-tumors-drive-treatment-resistance-.h00-159780390.html
• Immunotherapy biomarker study: https://www.mdanderson.org/newsroom/research-newsroom/researchers-find-new-biomarker-for-improved-immunotherapy-response-in-solid-tumors.h00-159780390.html
• End-of-life systemic therapy study: https://www.mdanderson.org/newsroom/research-newsroom/patients-receiving-anti-cancer-treatment-near-end-of-life-experience-higher-rates-of-hospitalization-ED-and-ICU-use-and-less-utilization-of-hospice.h00-159779601.html
• Computational method for precancer detection: https://www.mdanderson.org/newsroom/research-newsroom/-new-computational-method-improves-ability-to-detect-precancer.h00-159780390.html
• Hematopoietic cell transplantation in ALL: https://www.mdanderson.org/newsroom/research-newsroom/stem-cell-transplant-achieves-positive-outcomes-in-second-remission.h00-159780390.html
• Neuronal differentiation enzyme study: https://www.mdanderson.org/newsroom/research-newsroom/researchers-identify-enzyme-involved-in-driving-neuron-differentiation.h00-159779601.html
• Genetic markers in LBCL: https://www.mdanderson.org/newsroom/research-newsroom/researchers-identify-genetic-markers-that-affect-treatment-outcomes.h00-159780390.html

References:

• Cancer Cell publications on bacterial resistance and immunotherapy biomarkers, 2025
• Journal of Clinical Oncology on end-of-life care, 2025
• Nature Cell Biology on spatial transcriptomics, 2025
• American Journal of Hematology on stem cell transplantation outcomes, 2025
• Science Advances on KMT2D role in neuronal differentiation, 2025
• Journal for ImmunoTherapy of Cancer on CAR T cell therapy genetics, 2025

Keywords: cancer research; immunotherapy; immune response; immune system; antigens; cancer immunology; cancer; blood cancer; leukemia; metastasis; pancreatic cancer; skin cancer; neurons

The introduction of an inducible Cas9 system marks a pivotal advancement in the field. This innovative platform allows researchers to exert precise temporal control over the expression of Cas9, the endonuclease responsible for executing the genome cuts. This approach ensures that the gene editing process is synchronized perfectly with the establishment of a non-proliferative cell state, effectively mitigating one of the critical barriers to conducting successful screens in these challenging contexts. The nuances of this inducible system are vital for researchers aiming to probe deeper into the mechanisms of non-dividing cells, particularly within cancer diagnostics and treatment modalities.

To employ this technique, researchers begin by generating a cell line that expresses Cas9 under the control of an inducible promoter. This construction demands a thorough understanding of molecular cloning techniques, as well as familiarity with the principles of gene regulation. Once the inducible Cas9 cell line is established, it’s crucial to validate the system’s functionality. This procedure can be achieved through various methods, including but not limited to, quantitative PCR to confirm Cas9 expression levels and Western blotting for protein validation.

Simultaneously, it is essential to assess the editing efficiency following Cas9 activation. Flow cytometry emerges as a powerful tool in this context, enabling researchers to quantify the proportion of cells that have undergone successful editing based on the presence of fluorescent markers. By leveraging this technology, scientists can accurately measure the output of their CRISPR screens and tailor subsequent experiments to improve hit identification.

The implementation of this system is particularly significant in the context of senescence, a state characterized by stable cell cycle arrest. Senescent cells are known to contribute to various pathologies, including cancer, but remain relatively understudied due to historical limitations in research methodologies. The detailed workflow provided by the latest protocols allows for a comprehensive examination of senolytic targets, offering new opportunities to identify therapeutic avenues for eliminating undesirable senescent cells from tissues.

When conducting a CRISPR screen in senescent cells, researchers should keep in mind several optimization strategies. One critical factor is the selection of guide RNAs, which must be carefully curated to ensure a representative coverage of the target genome. The efficacy of guide RNA design plays a central role in the success of the experiment, as suboptimal designs are likely to undermine the overall results. Moreover, validation of guide RNA function through small-scale pilot studies could provide invaluable insights prior to embarking on large-scale screening efforts.

Another pivotal aspect of CRISPR screening in non-dividing cells is the timing of Cas9 activation. The ability to fine-tune the onset of editing allows researchers to mimic the natural progression of cellular states more accurately. This dynamic control not only facilitates the study of more complex biological processes but also enables the investigation of temporal factors that can influence gene interactions within non-proliferative environments.

As the scientific community rapidly seeks to understand the multifaceted roles of non-dividing cells, this CRISPR screening platform serves as a beacon of potential. The applications extend beyond cancer research and encompass fields such as stem cell differentiation, where cell fate decisions are intricately tied to non-proliferative states, as well as immune cell development, which relies heavily on the understanding of quiescence and activation processes over time.

Integrating this new framework into existing research paradigms will undoubtedly lead to breakthroughs across various biological disciplines. Indeed, the prospect of employing CRISPR to uncover mechanisms in both normal physiological processes and pathological conditions holds tremendous promise. Researchers are poised at the edge of an era where the interplay between genetic editing and non-proliferation could unveil pathways previously obscured by methodological limitations.

The forward momentum catalyzed by this inducible CRISPR platform is not merely an academic exercise; it carries substantial implications for therapeutic development. The ability to manipulate non-proliferative states could lead to innovative treatments that specifically target cancer stem cells or senescent cells, both of which pose significant hurdles in modern medical practice. By refining our understanding of cellular mechanisms, researchers will be better equipped to devise strategies that enhance patient outcomes and revolutionize personalized medicine.

As stakeholders in this process, the scientific community is urged to embrace these cutting-edge methodologies and build upon them with collaborative efforts across disciplines. In doing so, they can foster a culture of innovation that prioritizes not only technological advancements but also their applications in real-world scenarios. This continued dialogue between research and clinical practice will be essential in harnessing the full potential of CRISPR technology for the benefit of all.

In summary, the development and implementation of an inducible CRISPR-Cas9 screening platform create significant opportunities for deciphering the complexities of non-proliferative cellular states. By providing a rigorous framework that enhances the sensitivity and effectiveness of genomic editing approaches, researchers are now better empowered to explore previously unreachable questions in biology and medicine. The journey toward uncovering the roles of these elusive cellular states is just beginning, and the promise of CRISPR technology is set to unlock new frontiers in science and healthcare.

Subject of Research: Non-Proliferative Cellular States and CRISPR-Cas9 Screening

Article Title: Inducible CRISPR–Cas9 screening platform to interrogate non-proliferative cellular states

Article References:

Casagrande Raffi, G., Kuiken, H.J., Lieftink, C. et al. Inducible CRISPR–Cas9 screening platform to interrogate non-proliferative cellular states.
Nat Protoc (2025). https://doi.org/10.1038/s41596-025-01251-8

Image Credits: AI Generated

DOI:

Keywords: CRISPR, gene editing, senescence, cancer research, cellular states, inducible Cas9, flow cytometry, therapeutic development

ER-positive breast cancer represents a significant subset of breast cancer diagnoses globally, distinguished by its reliance on estrogen receptor signaling to drive tumor growth and survival. Despite advances in endocrine therapies, resistance mechanisms inevitably emerge, leading to therapeutic failure and disease progression. This new research identifies a previously underappreciated link between ESR1 activity and autophagy—a catabolic process essential for maintaining cellular homeostasis and stress tolerance—demonstrating that ESR1 exerts a suppressive control over p62/SQSTM1-dependent autophagy pathways in these tumor cells.

The autophagy receptor protein p62/SQSTM1 serves as a nodal regulator for selective autophagy, facilitating the degradation of ubiquitinated proteins and damaged organelles. Importantly, p62 is known to influence oxidative stress responses by mediating the turnover of pro-oxidant proteins and promoting cellular adaptation to stress. The study illuminates how suppression of ESR1 augments p62 expression and functionality, leading to a resurgence of autophagic flux. This process heightens cellular cleanses of oxidative damage and misfolded proteins, thereby sensitizing cancer cells to exogenous challenges such as reactive oxygen species and ionizing radiation.

Methodologically, the team employed an integrative approach combining molecular genetic techniques, cellular assays, and in vivo models to dissect the ESR1-p62 autophagy axis. By knockdown or pharmacological inhibition of ESR1, researchers observed restored autophagic activity in ER-positive breast cancer cell lines, accompanied by increased vulnerability to oxidative stress and radiotherapy-induced cytotoxicity. Conversely, enforced ESR1 expression attenuated autophagy, underscoring the receptor’s suppressive role in these pathways.

From a therapeutic perspective, this discovery unveils ESR1 as a dual-function target—beyond its canonical transcriptional regulation of proliferative genes, its modulation appears pivotal in orchestrating autophagy-mediated stress responses. This insight challenges established dogma, suggesting that endocrine therapies could be optimized or combined with autophagy-modulating agents to overcome resistant phenotypes and enhance treatment efficacy. Such combination strategies could achieve higher rates of tumor cell eradication by synergistically impairing adaptive survival mechanisms.

The intricate interplay between ESR1 signaling and autophagy impacts how ER-positive breast cancer cells navigate oxidative onslaughts, a situation commonly encountered during radiation therapy. Radiation generates high levels of reactive oxygen species (ROS), which induce DNA damage and cellular apoptosis; however, cancer cells frequently deploy autophagy to mitigate these insults, fostering radiotherapy resistance. By reinstating p62-dependent autophagy, ESR1 inhibition disrupts this protective shield, rendering cancer cells more susceptible to ROS-mediated apoptosis and improving overall treatment outcomes.

Additionally, the results elucidate the molecular cascades downstream of ESR1 that converge on autophagic machinery, including the modulation of key autophagy-related genes and signal transduction pathways. The study highlights the complex regulatory network where estrogen receptor influences autophagy markers such as LC3 and ATG proteins through transcriptional and post-translational mechanisms, aligning cellular catabolic processes with hormone receptor status and environmental stressors.

Importantly, the translational potential of this work extends to the clinical realm. The findings advocate for the development of next-generation ESR1 inhibitors with enhanced specificity for autophagy pathway restoration. Moreover, biomarkers related to p62/SQSTM1 expression and autophagic flux could serve as predictive tools for identifying patients likely to benefit from combined endocrine and autophagy-targeted therapies, paving the way for precision oncology approaches.

This paradigm-shifting research also prompts reevaluation of current therapeutic algorithms by integrating autophagy modulation as a cornerstone in managing ER-positive breast cancer. It calls attention to the balance between endocrine resistance mechanisms and cellular quality control systems, suggesting a synergistic vulnerability that could be tactically exploited. The prospect of overcoming radioresistance through autophagy reactivation offers a promising strategy to enhance the curative potential of combined modality therapies.

While this study primarily focuses on ER-positive breast cancer, the mechanistic insights into ESR1’s role in autophagy may have broader implications across hormone-driven malignancies. Future research is encouraged to explore whether similar autophagy regulatory networks exist in other estrogen-responsive cancers such as endometrial or ovarian tumors, potentially extending the impact of these findings beyond breast cancer.

In-depth molecular analysis revealed that ESR1 signaling dampens p62/SQSTM1 transcription and impairs its functional interactions with ubiquitinated cargo, which are critical for selective autophagy initiation. Reversing this repression through ESR1 targeting releases autophagic inhibition, facilitating enhanced clearance of cellular debris and promoting apoptotic cascades under stress conditions. Such mechanistic clarity strengthens the foundation for rational drug design aimed at modulating this axis.

Moreover, the study underscores the dynamic nature of cancer cell adaptation, whereby hormonal signaling pathways intersect with intracellular degradation systems to fine-tune survival responses. This crosstalk provides a fertile ground for discovering vulnerabilities unique to cancer cells, distinct from normal tissue counterparts, thereby minimizing off-target effects and improving therapeutic index.

The authors advocate a multidisciplinary approach to further refine ESR1-autophagy interactions, including protein structural studies and in vivo imaging of autophagic flux in clinical samples. These efforts will be crucial to translate preclinical observations into robust clinical interventions that can improve patient survival and quality of life in ER-positive breast cancer.

Ultimately, by charting a previously uncharted territory between estrogen receptor function and autophagy regulation, this seminal study sets a new standard for innovative cancer research. It challenges the research community to rethink existing biological paradigms and leverage molecular synergies for designing next-generation cancer therapeutics tailored to the complex biology of hormone-responsive tumors.

In conclusion, the restoration of SQSTM1-dependent autophagy through precise targeting of ESR1 constitutes a highly promising therapeutic strategy to sensitize ER-positive breast cancer cells to oxidative and radiation stress. This insight not only deepens our understanding of breast cancer biology but also offers an exciting clinical translational opportunity that could significantly improve outcomes for patients battling this prevalent and often formidable disease.

Subject of Research: Restoration of SQSTM1-dependent autophagy via ESR1 targeting in ER-positive breast cancer and its impact on sensitization to oxidative and radiation stress.

Article Title: Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.

Article References:
Yang, YF., He, ZJ., Kuo, HH. et al. Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress. Cell Death Discov. 11, 451 (2025). https://doi.org/10.1038/s41420-025-02755-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02755-8

Prostate cancer remains one of the leading causes of cancer-related morbidity and mortality in men worldwide. Despite advances in early detection and treatment, therapeutic resistance, particularly to androgen-deprivation therapy (ADT) and chemotherapy, often undermines clinical success. This resistance leads to disease progression, increased metastasis, and ultimately, treatment failure. The intricate interplay of molecular mechanisms driving this resistance has been a formidable challenge. However, miRNAs have now come to the forefront as key regulators modulating multiple pathways implicated in prostate cancer pathophysiology.

miRNAs function by binding to complementary sequences on messenger RNAs (mRNAs), repressing their translation or leading to their degradation. This regulatory capacity allows them to fine-tune cellular processes such as proliferation, apoptosis, differentiation, and stress responses. In prostate cancer, dysregulated miRNA expression profiles have been consistently observed, correlating with disease progression and response to therapy. Some miRNAs act as oncogenes (oncomiRs), promoting malignancy by suppressing tumor suppressor genes, while others act as tumor suppressors themselves.

The current research delves into the miRNA-mediated mechanisms that underpin resistance to conventional treatments. One emerging theme is the role of miRNAs in modulating androgen receptor (AR) signaling—the main driver of prostate cancer cell growth—especially in castration-resistant prostate cancer (CRPC), an advanced and treatment-refractory state of the disease. Aberrant expression of specific miRNAs can alter AR splice variants or co-regulator expression, effectively sustaining AR activity despite androgen deprivation.

Moreover, miRNAs influence critical pathways beyond AR, including those involved in DNA damage repair, epithelial-mesenchymal transition (EMT), and apoptosis evasion. For instance, certain miRNAs enhance DNA repair capabilities in tumor cells, rendering them less susceptible to genotoxic agents such as radiation and chemotherapeutic drugs. Others promote EMT, a plasticity program through which cancer cells gain increased motility and invasiveness, facilitating metastatic dissemination.

This multifaceted functionality presents miRNAs not only as biomarkers for disease prognosis and treatment response but also as compelling therapeutic targets. Recent advances in molecular therapeutics allow for the modulation of miRNA activity through mimics or inhibitors (antagomirs), offering precision tools to restore the balance of oncogenic and tumor-suppressive miRNAs within tumor microenvironments. These approaches hold the promise of overcoming drug resistance by dismantling the molecular defenses erected by malignant cells.

A particularly exciting aspect highlighted by researchers is the contribution of extracellular vesicles (EVs), such as exosomes, in transporting miRNAs from tumor cells to the surrounding stroma and distant tissues. This intercellular communication mechanism facilitates the remodeling of microenvironments to favor tumor survival and metastasis. Understanding and intercepting EV-mediated miRNA transfer could, therefore, curtail the metastatic cascade central to prostate cancer lethality.

Beyond therapeutic implications, miRNA signatures detectable in circulating fluids like blood and urine open avenues for non-invasive diagnostics. Liquid biopsies leveraging these molecular fingerprints can monitor disease dynamics in real-time, allowing clinicians to adapt treatment regimens proactively and detect emerging resistance before clinical relapse manifests.

The integration of high-throughput sequencing technologies and bioinformatics has accelerated the identification and functional characterization of cancer-associated miRNAs. This comprehensive molecular mapping facilitates the stratification of patients based on miRNA expression profiles, guiding personalized medicine initiatives. Future clinical trials incorporating miRNA-based interventions will be critical in validating their efficacy and safety in diverse patient populations.

Despite these promising developments, challenges remain in translating miRNA research into routine clinical practice. Delivery systems for miRNA therapeutics need refinement to ensure specificity, stability, and minimal off-target effects. Additionally, the intricate redundancy and cross-talk among miRNAs and their targets necessitate nuanced strategies capable of achieving therapeutic balance without disrupting normal cellular functions.

Nevertheless, the expanding repertoire of miRNA knowledge enriches the arsenal against prostate cancer, transforming previously opaque resistance mechanisms into decipherable and druggable pathways. By embracing miRNA biology, oncology is poised to usher in an era where precision therapies can outwit cancer’s adaptability, reduce metastatic burden, and dramatically improve patient outcomes.

In conclusion, the elucidation of miRNA-mediated resistance mechanisms in prostate cancer marks a watershed moment in cancer biology and therapeutics. These tiny RNA molecules wield outsized influence over tumor behavior, representing both the Achilles’ heel and a therapeutic goldmine in the battle against prostate malignancies. Continued interdisciplinary research and clinical innovation centered around miRNAs will be crucial in fulfilling the promise of targeted, resilient, and effective prostate cancer treatments.

Subject of Research: miRNA-mediated resistance mechanisms in prostate cancer and their implications for targeted therapy and metastatic progression.

Article Title: miRNA-mediated resistance mechanisms in prostate cancer: implications for targeted therapy and metastatic progression.

Article References:
Mostafa, M.M., El-Aziz, M.K.A. & Ellakwa, D.ES. miRNA-mediated resistance mechanisms in prostate cancer: implications for targeted therapy and metastatic progression. Med Oncol 42, 454 (2025). https://doi.org/10.1007/s12032-025-03006-7

Image Credits: AI Generated

The tumor microenvironment is not a passive backdrop but a dynamic ecosystem composed of cancer cells, stromal cells, immune infiltrates, extracellular matrix components, and a plethora of signaling molecules. These constituents engage in a sophisticated web of communication, facilitating adaptive metabolic rewiring that enables tumor cells to survive and proliferate even under harsh conditions such as hypoxia or nutrient scarcity. Metabolic flexibility manifests prominently in altered glucose metabolism, lipid signaling, and amino acid pathways, creating a metabolically hostile microenvironment that paradoxically supports tumor resilience.

Researchers are now leveraging state-of-the-art multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, to decode this complex system. These integrative analyses have revealed that cancer-associated fibroblasts (CAFs), immune cells such as tumor-associated macrophages (TAMs), and endothelial cells undergo distinct metabolic shifts that complement and support cancer cell metabolism. For instance, CAFs often switch to aerobic glycolysis—known as the Warburg effect—to produce lactate, which cancer cells then utilize as a fuel source via oxidative phosphorylation, illustrating a metabolic symbiosis within the tumor niche.

Another pivotal discovery entails the functional crosstalk mediated by metabolic intermediates and secreted factors. Lactate, previously considered a mere waste product, now emerges as a central oncometabolite facilitating immune evasion by promoting regulatory T-cell differentiation and suppressing cytotoxic T lymphocytes. Similarly, tumor-derived exosomes transport metabolic enzymes and microRNAs that reprogram recipient stromal and immune cells, thereby sculpting a microenvironment conducive to tumor progression and metastasis. Such bidirectional communication challenges the paradigm of targeting cancer cells alone, hinting at the necessity of intercepting these metabolic dialogues.

Hypoxia-inducible factors (HIFs) act as master regulators of metabolic adaptation within the TME. In hypoxic niches, HIF-driven transcriptional programs upregulate glycolytic enzymes and angiogenic factors, supporting vascular remodeling and nutrient supply. This adaptation, while aiding tumor survival, also imposes immunosuppressive effects through accumulation of adenosine and modulation of immune checkpoints. The metabolic penalties exacted by hypoxia thus ripple through the TME, altering cellular phenotypes and responses to therapy, offering insights for rational drug development.

The integration of metabolomic profiling has unveiled unique metabolic fingerprints that correlate with tumor aggressiveness and therapy response. Mass spectrometry-based analyses identify differential abundance of key metabolites such as glutamine, serine, and fatty acids, which serve as both diagnostic markers and therapeutic targets. Targeting these metabolic nodes, either through enzyme inhibition or nutrient restriction, demonstrates promising antitumor efficacy in preclinical models, underscoring the translational potential of metabolic interventions.

Importantly, the application of multi-omics data supports the stratification of patients based on their TME metabolic landscape, enabling precision oncology approaches. By mapping tumor-stroma interactions and metabolic fluxes, clinicians can predict resistance mechanisms and tailor combination therapies that simultaneously inhibit cancer cell metabolism and modulate the immune milieu. Such personalized strategies are expected to enhance efficacy while minimizing off-target toxicities, revolutionizing cancer treatment paradigms.

Emerging therapeutics aim to disrupt specific metabolic exchanges within the TME to dismantle the supportive infrastructure sustaining tumors. Inhibitors of monocarboxylate transporters (MCTs), responsible for lactate shuttling between stromal and cancer cells, have shown significant promise. These agents effectively starve cancer cells of critical metabolites and reprogram immune cells to a pro-inflammatory phenotype. Combining such metabolic inhibitors with immune checkpoint blockade holds tremendous potential to synergistically reinvigorate antitumor immunity.

Moreover, lipid metabolism reprogramming within the TME has gained attention for its role in modulating membrane dynamics, signaling cascades, and energy homeostasis. Alterations in fatty acid synthesis and beta-oxidation influence not only cancer cell proliferation but also macrophage polarization towards tumor-promoting phenotypes. Pharmacological targeting of key enzymes such as fatty acid synthase (FASN) and carnitine palmitoyltransferase 1 (CPT1) can reverse these effects, offering new therapeutic windows.

The multi-omics approach further unravels the complexity of amino acid metabolism in the TME. Cancer cells frequently depend on non-essential amino acids like glutamine and serine for nucleotide biosynthesis, redox balance, and epigenetic regulation. Concurrently, immune cells within the TME undergo metabolic constraints due to amino acid depletion, leading to impaired effector functions. Strategies to restore amino acid availability or inhibit cancer cell uptake pathways could rebalance this metabolic tug-of-war, enhancing immunosurveillance.

Epigenetic regulation in response to metabolic shifts also figures prominently in shaping the TME. Metabolites such as alpha-ketoglutarate and succinate function as cofactors or inhibitors of chromatin-modifying enzymes, influencing gene expression and cellular identity. These findings highlight an additional layer whereby metabolism affects tumor biology beyond energy production, providing further targets for intervention.

Beyond the cellular and molecular changes, metabolic reprogramming influences extracellular matrix remodeling and angiogenesis, contributing to tumor invasiveness. Enzymes like matrix metalloproteinases (MMPs) activated by metabolic cues degrade extracellular barriers, facilitating metastasis. Angiogenic switch induced by metabolic stress ensures sustained nutrient delivery but creates aberrant vessels that hinder drug penetration. Therapeutic strategies integrating metabolic modulation with normalization of the tumor vasculature promise improved drug delivery and efficacy.

As this field advances, artificial intelligence and machine learning emerge as indispensable tools for integrating vast multi-omics datasets, uncovering hidden metabolic networks and predictive biomarkers within the TME. Such computational frameworks accelerate hypothesis generation and validation, enabling rapid clinical translation. The convergence of technology and biology heralds a new era of precision oncology, where metabolic vulnerabilities are exploited to outmaneuver even the most recalcitrant tumors.

The study of metabolic reprogramming and functional crosstalk within the tumor microenvironment underscores that cancer is not merely a cellular disease but a systemic metabolic disorder. Holistic, multi-omics approaches provide unprecedented resolution, exposing the intricate dependencies that tumors forge with their surroundings. This knowledge enables the development of innovative combinatorial therapies aimed at metabolic circuits, immune modulation, and microenvironmental remodeling, potentially overcoming longstanding barriers in cancer treatment.

Ultimately, harnessing the insights from metabolic reprogramming within the tumor microenvironment offers hope for durable responses and long-term remission. By targeting the very processes that permit tumors to adapt and evade, this research opens transformative paths toward conquering cancer, promising a future where malignant growths can be controlled and even eradicated through precision metabolic interventions.

Subject of Research: Metabolic reprogramming and functional crosstalk within the tumor microenvironment and a multi-omics anticancer approach

Article Title: Metabolic reprogramming and functional crosstalk within the tumor microenvironment (TME) and A Multi-omics anticancer approach

Article References:
Mir, R., Javid, J., Ullah, M.F. et al. Metabolic reprogramming and functional crosstalk within the tumor microenvironment (TME) and A Multi-omics anticancer approach. Med Oncol 42, 373 (2025). https://doi.org/10.1007/s12032-025-02945-5

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The technological foundation of scRNA-seq lies in its ability to capture transcriptomic profiles of thousands to millions of individual cells, rather than averaging gene expression across bulk tissue samples. This single-cell resolution enables researchers to delineate the cellular heterogeneity within tumours, unmask rare cell types, and trace dynamic cellular states that collectively influence tumour progression and therapeutic resistance. Unlike traditional bulk RNA sequencing, which blurs distinctions between cell types, scRNA-seq reveals the nuanced cellular architecture and gene expression programs that underpin cancer biology, offering a powerful lens through which to assess intratumoral diversity.

Despite its roots in basic cancer biology, the clinical promise of scRNA-seq is steadily unfolding. The translation of these molecular insights into clinical applications could radically improve diagnostic precision, prognostic accuracy, and therapeutic stratification. As emphasized in a comprehensive recent review by Boxer et al., the body of scRNA-seq cancer research now coalesces around four central objectives with direct clinical implications: deciphering tumour heterogeneity, characterizing the tumour microenvironment, uncovering mechanisms of therapy resistance, and guiding personalized treatment strategies. Each of these goals directs the growing momentum in translational oncology towards more sophisticated, patient-tailored interventions.

Tumour heterogeneity remains a foremost challenge in oncology, often driving variable patient outcomes and complicating treatment. Single-cell sequencing elucidates this heterogeneity by capturing the spectrum of malignant cell subpopulations coexisting within a single tumour. Researchers have identified distinct, transcriptionally defined cancer cell states that correlate with metastatic potential, proliferative capacity, and therapeutic susceptibility. This deepened knowledge has revealed lineage plasticity and epigenetic reprogramming as central components of cancer evolution. Consequently, scRNA-seq stands to redefine tumour classification beyond histopathology and genomic mutations, paving the way for molecularly informed diagnoses.

Equally critical, the tumour microenvironment—once considered a passive backdrop—has been exposed as a dynamic and influential player in oncogenesis. Single-cell analysis has catalogued immune cell subsets, cancer-associated fibroblasts, endothelial cells, and myeloid populations that engage in complex crosstalk with malignant cells. These interactions modulate immune evasion, angiogenesis, and metastatic dissemination. Notably, dissecting the immune landscape at single-cell resolution has elucidated the mechanisms underpinning responses and resistance to immunotherapies. Such insights facilitate the identification of predictive biomarkers and novel immunomodulatory targets, offering avenues to potentiate clinical efficacy.

Resistance to therapy, encompassing both innate and acquired forms, is a central obstacle in achieving durable remissions. scRNA-seq has shed light on subclonal populations harboring resistance-associated transcriptional programs and survival niches within the tumour microenvironment that protect vulnerable cells from treatment-induced apoptosis. This granular analysis enables the tracing of evolutionary trajectories under therapeutic pressure, informing combination treatments and adaptive therapeutic regimens designed to preempt or overcome resistance. In the clinical context, monitoring such cellular dynamics through longitudinal sampling and single-cell profiling holds promise for dynamic therapy adjustment.

In guiding personalized therapies, scRNA-seq empowers clinicians and researchers to detect actionable molecular alterations and pathway activations present within specific tumour compartments. This approach surpasses the limitations of bulk sequencing by revealing cell-type-specific vulnerabilities, including rare but clinically actionable subpopulations. Personalized cancer vaccines, targeted therapies, and cell-based immunotherapies can be optimized with these data, enhancing precision medicine paradigms. Moreover, single-cell transcriptomics aids in patient stratification by identifying molecular signatures predictive of therapeutic response and adverse events.

Despite these groundbreaking advances, scRNA-seq technology currently faces notable technical and analytical challenges. Sample dissociation methods may induce transcriptional artifacts or selectively bias cell representation, while the high dimensionality of single-cell data demands sophisticated computational methodologies to integrate biological variation with technical noise. Additionally, the inherent cost and complexity of scRNA-seq limit its widespread clinical adoption at present. Addressing these limitations requires concerted interdisciplinary efforts encompassing improved experimental protocols, robust bioinformatics pipelines, and scalable platforms suitable for clinical laboratory environments.

Looking towards the future, integration of scRNA-seq with complementary modalities such as spatial transcriptomics, single-cell epigenomics, and proteomics promises to deliver a more holistic view of tumour biology and microenvironmental architecture. Spatial context, in particular, is critical as cell-to-cell interactions and tissue organization critically influence cancer progression and therapeutic responses, yet remain elusive in standard single-cell suspension analyses. Clinically viable multiplexed imaging combined with single-cell sequencing will likely unlock novel biomarkers and therapeutic targets embedded within the spatial tumor ecosystem.

The rise of machine learning and artificial intelligence applied to large-scale single-cell datasets is another impetus toward scalable clinical translation. These computational advances facilitate pattern recognition, cell identity classification, and predictive modeling that can accelerate the discovery of robust diagnostic and prognostic signatures. Automated workflows capable of integrating multi-omic single-cell data promise to redefine clinical decision-making by delivering actionable insights with increasing precision and speed.

It is becoming increasingly evident that future clinical oncology will rely heavily on multi-dimensional data incorporating single-cell transcriptomic profiles alongside genomic, proteomic, and clinical parameters. Digital pathology integrated with single-cell omics could enable routine molecular phenotyping, uncovering subclonal populations and microenvironmental features driving malignancy in real time. Such comprehensive molecular portraits hold the key to truly personalized cancer care, where treatments are dynamically tailored to individual tumour ecosystems.

In parallel, ongoing clinical trials are beginning to incorporate single-cell sequencing technologies to monitor tumour evolution, immune responses, and minimal residual disease. These studies will provide crucial evidence regarding the utility of scRNA-seq as a biomarker tool and guide its standardized incorporation into clinical workflows. Importantly, ethical and logistical considerations surrounding patient consent, data privacy, and equitable access will need to be thoroughly addressed as single-cell technologies transition into clinical settings.

In conclusion, the clinical applications of single-cell RNA sequencing in oncology stand poised at the cusp of revolutionizing cancer diagnostics and therapeutics. The technology’s unparalleled resolution reveals the vibrant and complex cellular tapestry of tumours, opening new paths for precision medicine tailored to the unique biology of each patient’s cancer. While technical hurdles remain, rapid advancements in experimental and computational techniques, along with growing clinical adoption, promise to transform scRNA-seq from a primarily investigational tool into a cornerstone of modern oncology practice. The decade ahead is likely to witness single-cell transcriptomics driving unprecedented improvements in cancer patient outcomes, making what was once the province of basic science a pivotal asset in the clinic.

Subject of Research: Clinical applications of single-cell RNA sequencing in patient-derived tumour samples

Article Title: Emerging clinical applications of single-cell RNA sequencing in oncology

Article References: Boxer, E., Feigin, N., Tschernichovsky, R. et al. Emerging clinical applications of single-cell RNA sequencing in oncology. Nat Rev Clin Oncol 22, 315–326 (2025). https://doi.org/10.1038/s41571-025-01003-3

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DOI: https://doi.org/10.1038/s41571-025-01003-3

Keywords: single-cell RNA sequencing, oncology, tumour heterogeneity, tumour microenvironment, therapy resistance, precision medicine, immuno-oncology, spatial transcriptomics

Colorectal cancer, one of the leading causes of cancer-related mortality worldwide, often employs mutations and signaling adaptations that enable it to evade the effects of molecular-targeted therapies. EGFR inhibitors, which block the receptor’s activity, initially exhibit promising clinical responses. However, resistance almost inevitably develops, blunting their long-term effectiveness. Until now, the molecular underpinnings of this resistance remained somewhat elusive, limiting the potential for tailored interventions.

The research team focused on dissecting the downstream signaling cascades triggered by EGFR, primarily the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) pathways, both of which have been implicated in cancer proliferation and survival. Prior studies suggested that both pathways might contribute to resistance mechanisms, making it challenging to determine which pathway represents the critical node. Using advanced molecular biology techniques and patient-derived models, the authors systematically analyzed the contributions of these pathways to therapy failure.

Their findings reveal a complex landscape in which ligand-driven activation of EGFR continues to fuel MAPK signaling despite the presence of EGFR inhibitors. This persistent MAPK activation appears to bypass therapeutic blockade, sustaining cell proliferation and survival. In contrast, PI3K signaling did not display a significant role in mediating resistance in the colorectal cancer models tested, refocusing attention on the MAPK axis for drug development.

A key aspect of the study involved identifying the source of ligands that reactivate EGFR in the presence of inhibitors. The researchers observed upregulated expression and secretion of multiple EGFR ligands, such as amphiregulin and epiregulin, in resistant cancer cells. These molecules effectively re-engage the receptor, circumventing the inhibitory actions of therapeutic antibodies or small molecule drugs. This ligand-mediated feedback loop represents a formidable barrier to sustained EGFR blockade.

The paper delves deeply into the molecular cross-talk and feedback mechanisms that underpin this resistance phenomenon. It highlights how ligand abundance modifies receptor dynamics and downstream kinase activation, reshaping the signaling environment in favor of tumor survival. This insight underscores the importance of considering extracellular ligand availability as an integral component of therapeutic design, rather than focusing solely on intracellular signaling nodes.

The study’s implications extend well beyond academic curiosity, as they provide actionable targets for improving clinical outcomes. By inhibiting ligand production or neutralizing ligand-receptor interactions, it may be possible to restore sensitivity to EGFR therapies. Indeed, the authors discuss potential combinatorial strategies that involve dual targeting of EGFR and its ligands or MAPK pathway components to overcome resistance.

Moreover, the research underscores the limitations of solely targeting PI3K in colorectal cancer resistance contexts. Despite its well-established role in other cancer types, PI3K inhibition did not yield significant improvements in overcoming EGFR therapy resistance here. These nuanced differences emphasize the necessity of cancer-type-specific approaches rather than broad-spectrum assumptions about pathway involvement.

From a technical perspective, the study employed a combination of phospho-proteomics, gene expression profiling, and functional assays in both in vitro and in vivo models. This integrative methodology enabled a comprehensive mapping of the resistance circuitry, lending robustness to the conclusions drawn. Additionally, patient-derived xenografts provided clinically relevant platforms that captured tumor heterogeneity, enhancing translational relevance.

The authors also investigated temporal dynamics of signaling activation during the onset and progression of resistance. Their data indicate that ligand-mediated MAPK reactivation occurs early and persists throughout treatment, suggesting that intervention strategies must be proactive rather than reactive. Timing appears crucial, as delayed targeting of these resistance loops might render subsequent attempts less effective.

Furthermore, the identification of ligand-induced resistance highlights potential biomarkers for early detection and monitoring of therapeutic failure. Measuring ligand levels or MAPK activation status in patient samples could guide treatment adjustments, enabling personalized medicine frameworks to flourish in colorectal cancer management.

This study represents a paradigm shift in our understanding of EGFR-targeted therapy resistance, emphasizing the centrality of extracellular ligand-mediated signaling rather than intracellular PI3K activity. It sets the stage for clinical trials testing novel inhibitors targeting ligand availability or MAPK signaling nodes, potentially transforming therapeutic landscapes.

In light of these findings, pharmaceutical development may shift towards biologics that neutralize EGFR ligands or small molecules that interrupt the MAPK cascade downstream of EGFR. This dual approach could thwart tumor adaptive responses and enhance treatment durability.

Intriguingly, the reported findings may also shed light on resistance mechanisms present in other solid tumors treated with EGFR inhibitors, such as non-small cell lung cancer or head and neck squamous cell carcinoma. Cross-cancer comparisons will be essential to determine the generalizability of ligand-activated MAPK signaling as a universal resistance mechanism.

The rigorous elucidation of these pathways opens multiple investigative angles, including exploring the role of tumor microenvironment in modulating ligand expression and receptor activation. Understanding how stromal cells or immune components contribute to this feedback could unlock further therapeutic interventions.

Ultimately, this landmark research published by Qu et al. not only pushes the boundaries of molecular oncology but also embodies the shift towards precision oncology—where detailed mechanistic insights directly inform smarter, more effective cancer treatments. The study empowers clinicians and researchers alike to rethink resistance paradigms and inspires new strategies for combating colorectal cancer’s formidable adaptability.

As the oncology community digests these revelations, ongoing efforts will focus on translating them into tangible clinical benefits, heralding a new era of hope for patients facing EGFR-resistant colorectal cancers. This research stands as a testament to the power of molecular dissection in unraveling the complexities of cancer and heralds targeted therapeutic advancements on the horizon.

Subject of Research: Resistance mechanisms to EGFR-targeted therapy in colorectal cancer, focusing on ligand-activated EGFR/MAPK signaling versus PI3K pathways.

Article Title: Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer

Article References:

Qu, X., Hamidi, H., Johnson, R.M. et al. Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer.
Nat Commun 16, 4332 (2025). https://doi.org/10.1038/s41467-025-59588-3

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