bims-enbcad Biomed News
on Engineering biology for causal discovery
Issue of 2025–12–28
fifteen papers selected by
Xiao Qin, University of Oxford
  1. Post-translational modifications of proteins: dynamic regulatory network and therapeutic targets of tumor immune escape in pan-cancer.
  2. The Emerging Triad in Cancer and Aging: Cellular Senescence, Microbiome, and Tumor Microenvironment.
  3. Modeling developmental morpho-dynamics at single-cell resolution.
  4. Tissue maps in motion.
  5. Interaction of intratumoral microbiota with the tumor immune microenvironment and its impact on cancer progression.
  6. Targeting cancer stem cell plasticity and tumor microenvironment crosstalk: a comprehensive review.
  7. Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer.
  8. Artificial Intelligence in Organoid-Based Disease Modeling: A New Frontier in Precision Medicine.
  9. SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications.
  10. Interferons as therapeutic orchestrators of cancer stem cell plasticity and therapy response.
  11. Survival implications of the age-associated tumor and normal adjacent tissue microbiome among colorectal cancer patients.
  12. Current Status and Future Challenges of Liquid Biopsy.
  13. Macrophages in Colorectal Cancer: from Normal Mucosa to Distant Metastasis: Beyond the M1/M2 Paradigm.
  14. Immune and Immune-Integrated Organoids as NextGeneration Platforms for Disease Modeling.
  15. Targeting γδ T cells for immunotherapies against colorectal cancer.
  1. Crit Rev Clin Lab Sci. 2025 Dec 24. 1-34
    Post-translational modifications of proteins: dynamic regulatory network and therapeutic targets of tumor immune escape in pan-cancer.
    Qilu Yan, Qingqing Zhai, Shuyang Yu, Wangzheqi Zhang.
      Post-translational modifications (PTMs) are critical regulators of protein function. Nearly two-thirds of all human proteins contain at least one PTM. These PTMs introduce covalent modifications, which modulate protein activity, location, and interactions. Further, PTMs are essential for understanding both physiological homeostasis and pathophysiology, and they play a key role in tumorigenesis and cancer development. Tumor immune evasion depends on dysregulated immune homeostasis caused by interactions between tumor cells and immune cells in the tumor microenvironment (TME). In this context, PTMs have emerged as one of the key regulators. From a pan-cancer perspective, PTMs remodel the tumor immune microenvironment through diverse mechanisms. The inability to regulate these processes is a common factor contributing to immune evasion in various cancers. It also facilitates crosstalk between tumor cells and components of TME, which in turn influences the response to immunotherapy. Because PTMs are dysregulated in cancers and can be reversed through drugs, they are attractive therapeutic targets. Small-molecule modulators of PTMs have the potential to reprogram the immune microenvironment and improve immune checkpoint blockade responses. Importantly, wide-ranging signal exchange networks between PTMs collectively increase tumoral immune phenotypic diversity and reveal new shared mechanisms of pan-cancer immune evasion. Recent studies show that the ways tumor cells change their surface proteins are driven by alterations in the tumor-immune environment. Further work could lead to strategies to treat many different cancers. Targeting PTM networks may overcome immune tolerance and significantly improve the clinical prognosis of cancer patients.
    Keywords:  PTMs; Post-translational modifications; antigen presentation; crosstalk mechanism; dynamic regulation; pan-cancer; tumor immune evasion
    DOI:  https://doi.org/10.1080/10408363.2025.2598380
  2. Aging Dis. 2025 Dec 21.
    The Emerging Triad in Cancer and Aging: Cellular Senescence, Microbiome, and Tumor Microenvironment.
    Xi Gong, Shaogang Wang, Qidong Xia.
      Aging is accompanied by a marked increase in cancer incidence and mortality, yet most studies still consider cellular senescence, the tumor microenvironment, and the microbiome as largely separate axes. Here, we propose an integrative triad framework in aging-related cancers in which cellular senescence, tumor microenvironment (conceptualized here as part of a broader tumor microecology), and the microbiome dynamically interact to shape tumor initiation, evolution, and treatment response. We summarize how senescent cells, via context-dependent senescence-associated secretory phenotypes (SASPs), remodel stromal, immune, and metabolic niches in aging hosts and how gut and intratumoral microbiota both induce and are reshaped by senescence. Focusing on colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC), together with pan-cancer transcriptomic and microbiome analyses. We highlight disease and subtype-specific patterns in which senescence signatures, immune contexture, and microbial features co-stratify prognosis and therapeutic outcomes, and integrate pan-cancer transcriptomic and microbiome analyses to illustrate shared and divergent triad configurations across tumor types. Finally, we discuss the therapeutic implications of this triad, including timing-dependent use of senolytics and senomorphics, diet and microbiome-targeted interventions, fecal microbiota transplantation (FMT), and the ecological risks of antibiotics, particularly in multimorbid older patients. We argue that triad-informed biomarkers and trial designs integrating senescence, microenvironment, and microbiome readouts will be important for mechanism-based, age-adapted cancer prevention and therapy in older adults, especially those with CRC, HCC, and PDAC.
    DOI:  https://doi.org/10.14336/AD.2025.1495
  3. Nat Methods. 2025 Dec 22.
    Modeling developmental morpho-dynamics at single-cell resolution.
      
    DOI:  https://doi.org/10.1038/s41592-025-02989-5
  4. Nat Methods. 2025 Dec 24.
    Tissue maps in motion.
    Miriam Osterfield.
      
    DOI:  https://doi.org/10.1038/s41592-025-02950-6
  5. Front Oncol. 2025 ;15 1609889
    Interaction of intratumoral microbiota with the tumor immune microenvironment and its impact on cancer progression.
    Yan Tingting, Zhu Xiaoling, Zhang Yu, Luo Yan, Luo Yang, Shang Xueqin, Tang Shikai.
      The intratumoral microbiota, a critical component of the tumor microenvironment (TME), has been demonstrated to significantly impact tumor progression and therapeutic outcomes. Research indicates that intratumoral microbes can affect tumorigenesis, metastasis, and therapeutic response through various mechanisms, such as inducing DNA damage, activating oncogenic signaling pathways, and modulating immune responses. Furthermore, the microbiota exerts dual regulatory effects on the tumor immune microenvironment (TIME), either enhancing anti-tumor immunity or promoting immunosuppression, thereby presenting novel targets for cancer therapy. In this paper, we conduct a review of the origin and composition of the intratumoral microbiota and its dynamic interactions with the TME by synthesizing data from multiple cancer studies. This review elucidates the complex role of the microbiota within the TIME and explores its potential for clinical application.
    Keywords:  antitumor immunity; immune cells; immunosuppression; intratumoral microbiota; tumor immune microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1609889
  6. Discov Oncol. 2025 Dec 21.
    Targeting cancer stem cell plasticity and tumor microenvironment crosstalk: a comprehensive review.
    Mutaz Jamal Al-Khreisat, Waleed K Abdulsahib, Ihsan Khudhair Jasim, H Malathi, Priya Priyadarshini Nayak, D Alex Anand, Gunjan Mukherjee, Aashna Sinha, Oybek Ruziyev.
      
    Keywords:  Cancer stem cells; Plasticity; Precision oncology; Therapeutic resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-04297-y
  7. Front Immunol. 2025 ;16 1692382
    Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer.
    Clara Sánchez-Menéndez, Jaime Rodríguez-Pérez, Daniel Fuertes, Valentina Leguizamon, María González-Sanmartín, Elena Mateos, Miguel Cervero, Esther San José, Gonzalo Sanz, Edurne Álvaro, Araceli Ballestero-Pérez, Marc Martí-Gallostra, José Antonio Rueda, Elena Hurtado-Caballero, Carlos Pastor, Francesc Balaguer, Antonino Spinelli, Jorge Martínez-Laso, Montserrat Torres, José Perea, Mayte Coiras.
       Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. While screening has reduced incidence in older adults, cases of early-onset CRC (EOCRC), diagnosed before age 50, are rising, highlighting the need to understand its unique biology. Immune responses, particularly T-cell infiltration measured by the tumor-based Immunoscore, are known predictors of CRC prognosis, but less is known about systemic immune differences by age at diagnosis.
    Methods: Peripheral blood mononuclear cells (PBMCs) from EOCRC (n=19) and late-onset CRC (LOCRC; n=19) participants recruited in Madrid (Spain) were analyzed for immune cell phenotypes, exhaustion markers, soluble cytokines, and metabolic activity.
    Results: Our study revealed distinct peripheral blood immune profiles differentiating EOCRC from LOCRC. EOCRC patients exhibited a heightened proinflammatory environment, with increased functional capacity of CD4+ Th1, Th9, and Th17 subsets to produce IFNg, IL-9, and IL-17A, respectively, and increased plasma levels of IFNg and CXCL8/IL-8. This suggests an active but potentially ineffective immune response. Conversely, LOCRC patients showed hallmarks of immunosenescence and chronic inflammation, including impaired cytokine production, higher frequencies of CD8+ Tgd and Th22 cells, and increased plasma CCL13/MCP-4, consistent with tissue remodeling and immune suppression. Biomarkers distinguishing EOCRC included reduced Th22 and CD8+ Tgd cell frequencies and higher NKT-like cells with increased IL-13 production by Th22 cells.
    Conclusions: EOCRC and LOCRC involved different immune mechanisms, where EOCRC showed an altered proinflammatory environment with preserved regulatory pathways, while LOCRC reflected age-related immune decline and inflammaging. Peripheral blood immune profiling offers a minimally invasive liquid Immunoscore for early detection and enables personalized immunotherapies for age-related immune landscapes, particularly benefiting younger individuals at risk of EOCRC.
    Keywords:  T-cell subsets; colorectal neoplasms; cytokine profiling; early diagnosis; immune biomarkers; immune response
    DOI:  https://doi.org/10.3389/fimmu.2025.1692382
  8. Biomimetics (Basel). 2025 Dec 17. pii: 845. [Epub ahead of print]10(12):
    Artificial Intelligence in Organoid-Based Disease Modeling: A New Frontier in Precision Medicine.
    Omar Balkhair, Halima Albalushi.
      Organoids are self-organizing three-dimensional (3D) cellular structures derived from stem cells. They can mimic the anatomical and functional properties of real organs. They have transformed in vitro disease modeling by closely replicating the structural and functional characteristics of human tissues. The complexity and variability of organoid-derived data pose significant challenges for analysis and clinical translation. Artificial Intelligence (AI) has emerged as a crucial enabler, offering scalable and high-throughput tools for interpreting imaging data, integrating multi-omics profiles, and guiding experimental workflows. This review aims to discuss how AI is reshaping organoid-based research by enhancing morphological image analysis, enabling dynamic modeling of organoid development, and facilitating the integration of genomics, transcriptomics, and proteomics for disease classification. Moreover, AI is increasingly used to support drug screening and personalize therapeutic strategies by analyzing patient-derived organoids. The integration of AI with organoid-on-chip systems further allows for real-time feedback and physiologically relevant modeling. Drawing on peer-reviewed literature from the past decade, Furthermore, CNNs have been used to analyze colonoscopy and histopathological images in colorectal cancer with over 95% diagnostic accuracy. We examine key tools, innovations, and case studies that illustrate this evolving interface. As this interdisciplinary field matures, the future of AI-integrated organoid platforms depends on establishing open data standards, advancing algorithms, and addressing ethical and regulatory considerations to unlock their clinical and translational potential.
    Keywords:  3D; artificial intelligence; disease modeling; organoid; stem cell
    DOI:  https://doi.org/10.3390/biomimetics10120845
  9. Front Immunol. 2025 ;16 1711015
    SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications.
    Juanjuan Wang, Ya Wang, Yuqing Liu, Rongcun Yang.
      Secreted phosphoprotein 1 (SPP1+) macrophages are a recurrent and functionally critical immune cell subset across multiple cancer types. They drive adverse clinical outcomes by promoting immunosuppression, tumor invasion, metastasis, and therapy resistance. Given their prevalence and pivotal role, SPP1+ macrophages have become a major focus in cancer immunology and a promising target for therapeutic development. SPP1+ macrophages have been identified in a wide range of human malignancies through single-cell RNA sequencing and spatial transcriptomics studies. Their differentiation and maintenance are strongly influenced by reciprocal cellular interactions and hypoxic conditions within the tumor microenvironment (TME). Within the tumor microenvironment (TME), SPP1+ macrophages promote tumor progression by interacting with cancer-associated fibroblasts (CAFs) and helping to form a physical barrier that restricts immune cell infiltration into the tumor core. Specifically, they impair the recruitment of CD8+ T cells and promote T cell exhaustion (TEX). In this review, we focus on recent advances in understanding the differentiation of SPP1 macrophages in hypoxic tumor microenvironment and the role of SPP1+ macrophages in immunosuppression and their therapeutic implications in cancer. Targeting this subset of macrophages has emerged as a highly promising therapeutic strategy, with several approaches demonstrating encouraging results in preclinical models.
    Keywords:  SPP1+ macrophages; T cell exhaustion; cancer therapy; osteopontin; physical barrier
    DOI:  https://doi.org/10.3389/fimmu.2025.1711015
  10. Cytokine Growth Factor Rev. 2025 Dec 15. pii: S1359-6101(25)00166-2. [Epub ahead of print]87 102-112
    Interferons as therapeutic orchestrators of cancer stem cell plasticity and therapy response.
    Deepakshi Kasat, Sophia Hidalgo, Lu Wang, Jack D Bui, Magalie Dosset.
      Cancer stem cells (CSCs) represent a small but critical subset of tumor cells characterized by their inherent self-renewal ability, differentiation potential, and resistance to cancer therapies. Their capacity to reversibly transition between a stem-like and differentiated state, together with their ability to enter into quiescence, are key determinants of their contribution to tumor initiation, tumor progression, metastasis, and cancer recurrence. Among the various factors in the tumor microenvironment, increasing evidence suggests that interferons (IFNs) are key extrinsic modulators of CSC fate. Although type I (IFN-α/β) and type II (IFN-γ) IFNs have long been recognized for their antitumor properties, recent studies indicate that IFN-signaling may also facilitate CSC induction and maintenance. In this review, we summarize and critically assess our current understanding of the complex roles of IFNs in governing CSC survival, plasticity, and immunogenicity. We discuss how IFN-signaling thresholds, signaling duration, and intrinsic CSC regulatory networks determine whether IFNs suppress CSCs or instead reinforce stemness. By bridging mechanistic insights with therapeutic potential and clinical outcomes, we highlight emerging opportunities to exploit IFN pathways for improved biomarkers and therapeutic strategies to overcome CSC-driven resistance.
    Keywords:  Biomarkers; Cancer stem cells; Cancer therapy; IFN signaling; Immune checkpoint therapy; Tumor resistance
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.12.008
  11. Gut Pathog. 2025 Dec 23. 17(1): 109
    Survival implications of the age-associated tumor and normal adjacent tissue microbiome among colorectal cancer patients.
    Maria F Gomez Morales, Stephanie R Hogue, Scott Pitcher, Daniel Jeong, Ivana Radosavljevic, Amalia Stefanou, Seth I Felder, Jessica R Burns, Scot E Dowd, Emily Vogtmann, Rashmi Sinha, Liang Wang, Xuefeng Wang, Jennifer B Permuth, Cynthia L Sears, Shaneda Warren Andersen, K Leigh Greathouse, Jacob K Kresovich, Mark S Friedman, Erin M Siegel, Doratha A Byrd.
       BACKGROUND: CRC incidence is rising among individuals younger than 50 years of age, with significant gaps in our understanding of the composition of the tissue microbiome across the age spectrum. The microbiome of tumors and normal adjacent tissue among colorectal cancer (CRC) patients may provide critical insights into the tumor microenvironment and CRC prognosis.
    METHODS: We characterized the tumor and normal adjacent tissue microbiome of early-onset (EoCRC, n = 46) and frequency-matched later-onset (LoCRC, N = 101) CRC patients who underwent surgery at Moffitt Cancer Center. We extracted DNA from archival tissue from 147 patients and sequenced the 16 S rRNA gene. We estimated the relative abundance of a priori and exploratory bacteria and alpha and beta diversity. We used multivariable linear regression models to estimate the association of age with the tumor and normal adjacent tissue microbiome. Then, we estimated associations of primarily age-associated microbiome metrics with overall survival using multivariable Cox proportional hazard models.
    RESULTS: In normal adjacent tissue, for every 10-year increase in age, there was a 1-SD higher relative abundance of a priori-selected Porphyromonas (Beta = 0.14, P = 0.03), Peptostreptococcus (Beta = 0.14, P = 0.03), and Prevotella (Beta = 0.13, P = 0.04). Fusobacterium and Bacillus were more abundant among EoCRC cases than LoCRC cases. In turn, Prevotella was associated with a 47% higher risk of mortality per 1-SD increase (95% CI = 1.19, 1.81; P < 0.001). Fusobacterium was not associated with mortality, but Bacillus was inversely associated with mortality.
    CONCLUSION: We found that age at diagnosis was associated with the relative abundance of several bacteria, including oral-origin genera that were previously CRC-associated, in CRC normal adjacent tissue. In turn, some of these bacteria were associated with survival, suggesting potential age-related mechanisms underlying associations of the microbiome with survival.
    TRANSLATIONAL RELEVANCE OF THE WORK: Emerging evidence has highlighted the important role of the microbiome in colorectal cancer (CRC). Since the 1990s, there has been an increase in cases of early-onset colorectal cancer. However, there is still a limited understanding of the risk factors contributing to this rise. Investigating the associations between the microbiome of tumors and normal adjacent tissue in relation to aging offers a unique perspective on potential modifiable factors. Notably, our study has shown that age-related changes in the abundance of bacteria originating from the oral cavity, such as Porphyromonas, Peptostreptococcus, and Prevotella, are linked to CRC prognosis. These findings suggest that changes in the tissue microbiome with age may serve as prognostic markers for CRC and could help inform future prevention strategies that consider dietary and oral health interventions.
    Keywords:  Age-associated microbiome changes; Early-onset colorectal cancer; Tissue microbiome
    DOI:  https://doi.org/10.1186/s13099-025-00773-6
  12. Cells. 2025 Dec 16. pii: 2000. [Epub ahead of print]14(24):
    Current Status and Future Challenges of Liquid Biopsy.
    Shuta Ohara, Kenichi Suda.
      Liquid biopsy has rapidly advanced as an innovative tool in precision oncology, allowing clinicians to capture the dynamic molecular and/or quantitative changes in tumors with minimal invasiveness [...].
    DOI:  https://doi.org/10.3390/cells14242000
  13. J Cancer. 2026 ;17(1): 157-176
    Macrophages in Colorectal Cancer: from Normal Mucosa to Distant Metastasis: Beyond the M1/M2 Paradigm.
    Sergii Pavlov, Esraa Ali, Filip Ambrozkiewicz, Wenjing Ye, Marie Rajtmajerová, Václav Liška, Kari Hemminki, Andriy Trailin.
      Colorectal cancer (CRC) is the third most common malignancy and leading cause of mortality worldwide. Tumor microenvironment (TME) strongly influences CRC growth, immune evasion, and metastasis. Among various immune cells, tumor-associated macrophages (TAMs) act as key regulators of cancer progression. Although traditionally classified as M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor), single-cell RNA sequencing and spatial transcriptomics have revealed that macrophage phenotypes exist along a continuum, challenging the classic dichotomy. This review investigates macrophages throughout CRC development, from normal mucosa to adenoma, primary tumor, and liver metastasis. Early adenomas feature M1-like macrophages that drive local inflammation, whereas advanced adenomas and invasive CRC comprise M2-like macrophages promoting angiogenesis, extracellular matrix remodeling, and immunosuppression. TAMs are crucial in CRC metastasis, particularly to the liver. M2-polarized Kupffer cells express CD206 and CD163, secrete hepatocyte growth factor, and activate PI3K/AKT signaling, thus aiding extravasation, survival, and proliferation of metastatic cells. They also foster lymphangiogenesis and immunosuppression through release of IL-10 and TGF-β. CRC's consensus molecular subtype (CMS) impacts the profile of TAMs: CMS1 (microsatellite instability-high) tumors typically harbor an anti-tumor M1 macrophages, while CMS4 (mesenchymal) tumors are enriched in M2-like TAMs, which facilitate stromal remodeling and angiogenesis, ultimately contributing to a poor prognosis. Spatial distribution also matters. Abundant M1 macrophages at the invasive margin correlate with better outcomes, whereas M2 macrophages in tumor centers and metastatic sites drive disease progression. Some CD206+ macrophages, however, support vascular normalization, which can limit metastasis. These findings underscore the complexity of TAMs in CRC and highlight the necessity of multi-marker phenotyping. Given the limitations of the M1/M2 paradigm, advanced techniques such as spatial transcriptomics and single-cell RNA sequencing offer novel insights into TAM heterogeneity. Future therapeutic strategies targeting TAMs, including metabolic reprogramming, epigenetic modulators, and immune checkpoint inhibitors, hold promise for improving CRC patient outcomes by shifting the balance toward an anti-tumor immune response.
    Keywords:  M1/M2 markers; adenoma-colorectal cancer-liver metastasis sequence; colorectal cancer; normal mucosa; prognostic significance.; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/jca.126772
  14. MedComm (2020). 2025 Dec;6(12): e70531
    Immune and Immune-Integrated Organoids as NextGeneration Platforms for Disease Modeling.
    Kimiya Rashidan, Malaksima Ayadilord, Ali Hazrati, Amirhossein Nazerian, Abbas Shafiee, Seyed Mahmoud Hashemi.
      Organoids are three-dimensional structures that closely resemble the architecture and functions of human organs, offering key advantages over traditional models by better replicating tissue complexity and cellular interactions. These systems have become invaluable tools for disease modeling, drug screening, and regenerative medicine applications. Despite this progress, their lack of immune components limits their usefulness in diseases where immune cells are central drivers of pathology and therapy. The absence of an immune system within organoids limits their physiological relevance, particularly for cancer, inflammation, and autoimmunity research. Immune cell-containing organoids provide a comprehensive platform for immunotherapy, host-pathogen interactions, regeneration, and immune disorders. This review first highlights the transformative potential of immune cell-containing organoids across cancer, infection, inflammation, autoimmunity, regeneration, and the modeling of primary lymphoid organs. It then examines current strategies for integrating immune cells into organoids, the variety of immune cell sources employed, and the challenges in maintaining immune cell function. Finally, the role of bioengineering, biobanking, and artificial intelligence in overcoming existing limitations and enhancing immune system modeling is discussed. Overall, this study positions immune cell-containing organoids as powerful platforms for translational research and precision medicine.
    Keywords:  cancer; immune cell; inflammation; organoid; pluripotent stem cell; regenerative medicine
    DOI:  https://doi.org/10.1002/mco2.70531
  15. Trends Immunol. 2025 Dec 20. pii: S1471-4906(25)00308-4. [Epub ahead of print]
    Targeting γδ T cells for immunotherapies against colorectal cancer.
    Joanna Mikulak, Paolo Marzano, Valentina Cazzetta, Domenico Mavilio.
      The advancement of immunotherapy faces significant challenges, including extending its benefits to a growing number of patients and enhancing its efficacy across different tumor types. In this context, γδ T cells emerge as particularly promising candidates owing to their distinctive biological features such as MHC-independent activation, potent cytotoxicity, and capacity to bridge innate and adaptive immunity. Recently, advanced single-cell techniques have allowed detailed γδ T cell characterization in the tumor microenvironment (TME) and have emphasized their heterogeneity, mechanisms of activation, and response to immune checkpoint blockade (ICB). This review provides a comprehensive summary of recent advances in understanding γδ T cells in colorectal cancer (CRC), with a particular emphasis on their prognostic and therapeutic relevance in both primary tumors and metastatic disease.
    Keywords:  colorectal cancer; immunotherapy; liver metastases; single-cell RNA sequencing; tumor microenvironment; γδ T cells
    DOI:  https://doi.org/10.1016/j.it.2025.11.009
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