bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–05–17
fourteen papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. CD8+ T cells turn resilient under stress.
  2. Upregulation of ADAM10 reinforces CD8+ T cells toward exhaustion in the TME.
  3. SLA2 is Associated With Immune evasion and Exhaustion of CD8+ T Cells in Gastric Cancer.
  4. MicroRNA-targeted reprogramming of CD8+ T cells against cancer.
  5. An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer.
  6. Head-to-head comparison of nuclear imaging approaches to quantify tumor CD8+ T-cell infiltration.
  7. Protocol for mapping tumor infiltration by murine T cells using multiplex immunofluorescence.
  8. Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
  9. Understanding immune checkpoint inhibitor efficacy through spatial decoding of the lung cancer tumor immune microenvironment.
  10. Metabolic reprogramming as a driver of immune escape in melanoma: implications for immunotherapy.
  11. Spatial Biology Evolution: Past, Present and Future of Mapping Life in Context.
  12. Multiomics Characterization of GCSH + Macrophages Reveals Therapeutic Vulnerabilities and Immune-Metabolic Crosstalk in Triple-Negative Breast Cancer.
  13. Metabolic pattern changes of macrophages during cancer development and progression.
  14. Harnessing Cancer Stem Cells and 3D Organoids in Unravelling Spatial and Cellular Heterogeneity in Cancer.
  1. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  2. Int Rev Immunol. 2026 May 13. 1-16
    Upregulation of ADAM10 reinforces CD8+ T cells toward exhaustion in the TME.
    Ahmed M E Abdalla, Yu Miao, Yasir A Taha, Ning Meng, Chenxi Ouyang.
      Using cytotoxic CD8+ T cell-mediated cellular immunity has shown considerable efficacy in cancer treatment. However, the effectiveness of these cells against solid tumors is limited by the presence of an immunosuppressive tumor microenvironment (TME), which constitutes complex networks of regulatory pathways and resistance mechanisms. Given its critical role in TME deterioration through shedding of immunosuppressive molecules from tumor and immune cell surfaces, the upregulation of A Disintegrin and Metalloproteinase 10 (ADAM10) expression can reinforce CD8+ T cells into a state of exhaustion. This paper highlights the influence of ADAM10 and its proteolytic products on the primary pathways of CD8+ T cell exhaustion, including the expression of immune checkpoint molecules and modification across CD8+ T cell transcriptional, metabolic, and nutritional states. We remain optimistic about the critical role of ADAM10 in cytokine-induced T cell exhaustion, recruitment of immunosuppressive cells into the TME, and CD8+ T cell death/survival. Gaining significant insights into these processes may offer new strategies to advance CD8+ T cell-mediated cancer therapy.
    Keywords:  +T cell exhaustion; +T cell therapy; CD8; solid tumors; tumor microenvironment (TME); upregulation of ADAM10 expression
    DOI:  https://doi.org/10.1080/08830185.2026.2669732
  3. J Cell Mol Med. 2026 May;30(9): e71164
    SLA2 is Associated With Immune evasion and Exhaustion of CD8+ T Cells in Gastric Cancer.
    Yujia Zhang, Xiaoyan Li, Rongchao Xiang.
      The Src-like adaptor 2 (SLA2) functions as a negative regulator of T cell receptor signalling. However, its involvement in the tumour microenvironment (TME) of gastric cancer (GC) remains unexplored. In this study, we found that SLA2 expression was significantly elevated in GC tissues, and a high level of SLA2 was associated with poor prognosis in GC patients. Bioinformatics analyses revealed a close association between SLA2 and TME in GC. Single-cell RNA sequencing analysis indicated that SLA2 was significantly enriched in CD8+ T cells in GC tissues. Functional validation demonstrated that SLA2 overexpression contributed to the exhaustion of CD8+ T cells by suppressing their proliferation, upregulating the expression of exhaustion markers, reducing the secretion of effector cytokines (IFN-γ and TNF-α) and impairing cytotoxic function. SLA2 knockdown in in vitro-generated exhausted CD8 T cells significantly alleviated T cell exhaustion. Mechanistically, we found that inverse promoter methylation and active histone marks (H3K27ac, H3K4me3 and H3K4me1) may regulate SLA2 expression. Our findings suggest that SLA2 may modulate the TME and promote immune evasion via CD8+ T cell exhaustion in GC.
    Keywords:  CD8+ T cells; SLA2; gastric cancer; immune evasion; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.71164
  4. Front Immunol. 2026 ;17 1770102
    MicroRNA-targeted reprogramming of CD8+ T cells against cancer.
    Yuchen Mao, Yujin Liu, Kaiyan Jing, Yiqing Shao, Kangping Yang, Jiaqiang Wu, Xianhuan Zhou, Heng Wang, Ziling Fang.
      This scoping review highlights the critical role of microRNAs (miRNAs) in mediating the bidirectional crosstalk between CD8+ T cells and tumor cells within the immunosuppressive tumor microenvironment (TME). Specific miRNAs (e.g., miR-155, miR-340-5p) orchestrate CD8+ T cell function by fine-tuning immune checkpoints (PD-1/PD-L1), metabolic reprogramming, and epigenetic states. Conversely, CD8+ T cells influence tumor behavior via exosomal miRNA transfer (e.g., miR-765). Our analysis reveals both pan-cancer mechanisms, such as PD-1/PD-L1 regulation, and tissue-specific miRNA functions (e.g., miR-143 in melanoma). To overcome translational challenges like off-target effects, innovative delivery strategies using lipid nanoparticles and engineered exosomes are being developed. This review provides a mechanistic framework for miRNA-mediated interactions, offers clinical insights for novel combination therapies, and assesses future directions, thereby advancing the development of precision immunotherapies.
    Keywords:  CD8+T cell; cancer; cellular pathway; immunology; microRNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1770102
  5. Oncoimmunology. 2026 Dec 31. 15(1): 2674362
    An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer.
    Lorenzo Lucantonio, Ludovica Schiano, Francesca Sozio, Andrea Kosta, Giovanna Peruzzi, Rosa Molfetta, Giuseppe Pietropaolo, Mattia Laffranchi, Antonio Francesco Campese, Giovanni Bernardini, Silvano Sozzani, Angela Gismondi, Angela Santoni, Giuseppe Sciumè, Stabile Helena, Cinzia Fionda.
      Colorectal cancer (CRC) treatment represents a major clinical challenge, with immunotherapy providing durable responses only in a minority of patients. A deeper understanding of CD8⁺ T cell exhaustion and its contribution to immune checkpoint inhibitor (ICI) responsiveness is essential for the development of more effective therapeutic strategies. Preclinical models that faithfully reproduce the immune landscape of human CRC are therefore critical to address these challenges. Here, we established a syngeneic organoid-based orthotopic CRC mouse model by transplanting quadruple mutant Apc⁻/⁻KrasG12D/+Trp53R172H/⁻Smad4⁻/⁻ (AKPS) intestinal organoids into the rectal submucosa of immunocompetent mice. Single-cell transcriptomic profiling revealed that CD8⁺ T cells represent the predominant leukocyte population within the tumor infiltrate and comprise populations transitioning toward dysfunction. Functionally, CD8⁺ T cell depletion led to increased tumor burden in orthotopic AKPS implants, underscoring their antitumor activity. Importantly, anti-PD-1 treatment increased the abundance of dysfunctional CD8⁺ T cell populations within AKPS tumors and reduced tumor growth, demonstrating the responsiveness of this model to ICIs. In contrast, subcutaneous implants of AKPS were infiltrated by mixed CD4⁺ and CD8⁺ T cell subsets, with CD8⁺ T cells exhibiting a markedly less dysfunctional profile, highlighting the limitations of heterotopic tumor models for studying antitumor immune responses. Together, our findings establish the AKPS orthotopic CRC model as a platform to dissect the molecular mechanisms of early CD8⁺ T cell dysfunction and to preclinically evaluate novel immunotherapeutic interventions in CRC.
    Keywords:  CD8+ T cell exhaustion; Colorectal cancer; immunotherapy
    DOI:  https://doi.org/10.1080/2162402X.2026.2674362
  6. Immunother Adv. 2025 ;5(1): ltaf027
    Head-to-head comparison of nuclear imaging approaches to quantify tumor CD8+ T-cell infiltration.
    Gerwin G W Sandker, René Raavé, Inês F Antunes, Milou Boswinkel, Lenneke A M Cornelissen, Gerben M Franssen, Janneke Molkenboer-Kuenen, Peter J Wierstra, Iris M Hagemans, Erik F J de Vries, Johan Bussink, Gosse J Adema, Martijn Verdoes, Erik H J G Aarntzen, Sandra Heskamp.
       Introduction: Many immunotherapies focus on (re)invigorating CD8+ T cell anti-cancer responses. Different nuclear imaging techniques have been developed to measure CD8+ T cell distributions. Comprehensive comparisons of in vivo and ex vivo T cell labeling methods with respect to tumor and normal tissue targeting and correlation with CD8⁺ T cell presence are lacking, but essential for accurate clinical interpretation. We performed a head-to-head comparison of three CD8+ T cell imaging approaches: 89Zr-labeled Fc-silent anti-CD8 antibody ([89Zr]Zr-anti-CD8-IgG2asilent), ex vivo 89Zr-labeled ovalbumin-specific CD8+ T cells ([89Zr]Zr-OT-I), and 18F-labeled IL2 ([18F]AlF-RESCA-IL2).
    Methods: B16F10/OVA tumor-bearing C57BL/6 mice (n = 10/group) underwent PET/CT imaging at 72 ([89Zr]Zr-anti-CD8-IgG2asilent), 24 and 48 h ([89Zr]Zr-OT-I), and 10 min ([18F]AlF-RESCA-IL2) pi. Subsequently, biodistribution analysis was performed, followed by flow cytometry to evaluate intratumoral CD8+ T cell numbers. Intratumoral radiolabel distributions were assessed by autoradiography and immunohistochemistry.
    Results: All approaches showed uptake in CD8-rich tissues, with preferential spleen targeting. Biodistribution analyses showed tumor uptake exceeded blood level for [89Zr]Zr-anti-CD8-IgG2asilent and [89Zr]Zr-OT-I. Furthermore, their tumor uptake correlated to intratumoral CD8+ T cells presence even though intratumoral distribution patterns differed significantly.
    Conclusion: [89Zr]Zr-anti-CD8-IgG2asilent and [89Zr]Zr-OT-I PET/CT imaging can evaluate intratumoral CD8+ T cell infiltration. [89Zr]Zr-anti-CD8-IgG2asilent might be suited for TME immunophenotyping, while ex vivo labeling visualizes tumor migration and invasion dynamics of tumor-specific T cells. [18F]AlF-RESCA-IL2 uptake did not correlate to the intratumoral CD8+ T cell presence. Here, we provide new insights to guide the selection of imaging strategies for assessing relevant immunotherapy-specific aspects of the TME and support the correct interpretation of clinical CD8 imaging.
    Keywords:  CD8-positive T-lymphocytes; PET/CT; anti-CD8 antibody; ex vivo labeled CD8+ T cells; interleukin-2
    DOI:  https://doi.org/10.1093/immadv/ltaf027
  7. STAR Protoc. 2026 May 14. pii: S2666-1667(26)00223-6. [Epub ahead of print]7(2): 104570
    Protocol for mapping tumor infiltration by murine T cells using multiplex immunofluorescence.
    Raymond J Lim, Camelia Dumitras, Kostyantyn Krysan, Linh M Tran, Samantha Man, Steven M Dubinett, Bin Liu.
      Here, we present a 7-plex immunofluorescence staining protocol that enables the spatial analysis of murine tumor tissues to investigate the complex interplay between immune cells and the tumor microenvironment. We used a sequential antibody labeling strategy that identifies CD4+ and CD8+ T cells and characterizes their activation and regulatory states. This protocol also maps T cell infiltration within tumors, allowing researchers to investigate immune cell distribution, interactions, and the dynamic biology of the tumor immune landscape in murine tumor models. For complete details on the use and execution of this protocol, please refer to Lim et al.1.
    Keywords:  Cancer; Cell Biology; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104570
  8. Transl Oncol. 2026 May 15. pii: S1936-5233(26)00146-4. [Epub ahead of print]69 102809
    Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
    Lexin Wang, Honglin He, Ke Su, Yunjing Gao, Ying Luo, Huanhuan Tan, Ziyang Liu, Ke Xu, Yi Li, Xiaosong Li.
       BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC.
    METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence therapeutic target in ccRCC. This computational prediction was validated through bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics to delineate NNMT-associated molecular and cellular programs. While the discovery phase highlighted endothelial-specific NNMT overexpression, we further validated the functional consequences of NNMT modulation using Caki-1 and A498 cell lines to model the downstream signaling cascades. Functional assays assessed impacts on proliferation, apoptosis, cytokine secretion (IL-6, IL-1β, TNF-α), and TGF-β pathway activity. Immune infiltration and T cell exhaustion signatures were evaluated across TCGA cohorts.
    RESULTS: Multi-omics profiling revealed that NNMT is specifically overexpressed in tumor-associated endothelial cells enriched for active TGF-β signaling and inflammatory cues. High NNMT expression strongly correlated with CD8⁺ T cell exhaustion, elevated apoptotic signaling, and immunosuppressive cytokine production. In functional validation, NNMT knockdown suppressed TGF-β activity, reduced pro-inflammatory cytokines, and restored CD8⁺ T cell infiltration and effector function. Mechanistically, NNMT loss shifted the BAX/Bcl-2 ratio toward apoptosis and increased cleaved caspase-3. Spatial transcriptomics confirmed that NNMT⁺ endothelial cells form an immunosuppressive niche in direct contact with exhausted T cells. We also found that I-BET-762, I-BET-151, PFI-1, and BMS-387032 can target and inhibit NNMT to reduce CD8⁺ T cell exhaustion.
    CONCLUSION: We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC.
    Keywords:  CD8⁺ T cell exhaustion; Clear cell renal cell carcinoma; Multi-Omics; NNMT; TGF-β signaling
    DOI:  https://doi.org/10.1016/j.tranon.2026.102809
  9. J Clin Invest. 2026 May 15. pii: e206316. [Epub ahead of print]136(10):
    Understanding immune checkpoint inhibitor efficacy through spatial decoding of the lung cancer tumor immune microenvironment.
    Tao Zou, John D Minna.
      Immune checkpoint inhibitors (ICIs) have improved patient outcomes substantially in non-small cell lung cancer (NSCLC). Despite considerable effort, our understanding of the features that predict for immunotherapy response and resistance in patients remains incomplete. In this issue of the JCI, Isomoto and colleagues utilized a multiplex IHC platform to profile the spatial organization of the lung cancer tumor immune microenvironment, enabling the identification of spatial immune features that correlate with immunotherapy efficacy. This study enhances our knowledge of the spatial organization of features impacting ICI efficacy by identifying a three-variable spatial composite - including CD73 upregulation in EGFR-mutant NSCLC - that substantially outperforms PD-L1 expression in predicting immunotherapy efficacy. Moreover, it establishes spatial proteomic profiling as a platform for generating therapeutic hypotheses that are actionable and mechanistic in NSCLC.
    DOI:  https://doi.org/10.1172/JCI206316
  10. Front Immunol. 2026 ;17 1805144
    Metabolic reprogramming as a driver of immune escape in melanoma: implications for immunotherapy.
    Hong Liang, Lina Han, Xiao Feng, Lian Zhang.
      Melanoma has long served as a paradigm for cancer immunotherapy due to its high immunogenicity and the transformative impact of immune checkpoint blockade. However, durable clinical benefit remains confined to a subset of patients, with primary and acquired resistance remaining common. This plateau highlights a central unresolved question: how melanoma evades immune-mediated elimination despite reinvigorated antitumor immunity. Immune escape in melanoma cannot be fully explained by defects in antigen presentation, interferon signaling, or checkpoint regulation alone. Increasing evidence identifies tumor-intrinsic metabolic reprogramming as a dominant driver of immune dysfunction. By rewiring glucose, amino acid, lipid, and mitochondrial metabolism, melanoma cells create a metabolically restrictive microenvironment that suppresses effector T and NK cell function while favoring regulatory and myeloid immunosuppressive states through nutrient competition, inhibitory metabolite accumulation, and metabolite-driven signaling. In this Review, we synthesize recent advances establishing metabolic reprogramming as an organizing principle of immune escape in melanoma. We integrate how tumor metabolic programs shape immune cell fate, function, and spatial organization, and how metabolic crosstalk between tumor and immune compartments generates immune-resistant niches that persist despite checkpoint blockade. We further discuss emerging therapeutic strategies that target metabolic vulnerabilities, alone or in rational combination with immunotherapy, to overcome resistance by reconditioning the metabolic context of antitumor immunity. By reframing metabolism as a governing axis rather than a secondary hallmark of melanoma, this Review provides a conceptual and translational framework for the development of mechanism-guided immunotherapies with durable clinical impact.
    Keywords:  immune escape; immunotherapy resistance; melanoma; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1805144
  11. Cells. 2026 Apr 22. pii: 743. [Epub ahead of print]15(9):
    Spatial Biology Evolution: Past, Present and Future of Mapping Life in Context.
    Alexander E Kalyuzhny.
      The life sciences are currently undergoing a serious transition from the reductive biochemical analysis of dissociated tissues to non-destructive "spatial forensics". In addition to discovering new molecules, we are moving towards finding out their precise tissue localization and performing in situ interrogation to uncover a biological logic within preserved cellular "neighborhoods". Our perspective is focused on exploring the spatial imperative, including the structural logic and "neighborhood effects" of the tissue microenvironment, which is a prerequisite to understanding cellular function in normal and in pathological conditions. Beginning with a historical foundation of the origins of histochemistry, dating back to the 19th century with pioneer botanist François-Vincent Raspail, we emphasize the technological metamorphosis, transitioning from classical immunohistochemistry to modern multi- and high-plex spatial multi-omics. A critical evaluation of the current operational landscape has been made, addressing the engineering strategies behind multiplexed immunofluorescence (mIF), the challenges of experimental design in spatial transcriptomics, and the functional symbiosis between targeted and unbiased spatial proteomics. There are many layers of genomic and proteomic information we have to consider in order to unravel the mechanisms underlying body function. If we learn how to combine all this information together, we will be able to better understand how cells communicate with each other and what disrupts their communication, leading to cancer and many other pathologies. It is obvious that by implementing spatial biology tools, it becomes possible to develop new medicines and treat diseases in the most efficient ways. At the same time, we realize that there is an urgent need to learn how to put data pieces together so that they blend seamlessly into a meaningful output, further transitioning spatial biology over time into a routine tool to cure for both common and rare diseases and improve our lives and health.
    Keywords:  IHC; cyclic immunofluorescence (CyCIF); fast fluidic exchange (FFeX); histochemistry; multiplexed immunofluorescence (mIF); sequential immunofluorescence (seqIF); spatial biology history; spatial omics; spatial proteomics (SP); spatial transcriptomics (ST); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cells15090743
  12. Hum Mutat. 2026 ;2026 7893655
    Multiomics Characterization of GCSH + Macrophages Reveals Therapeutic Vulnerabilities and Immune-Metabolic Crosstalk in Triple-Negative Breast Cancer.
    Jiahao Ge, Ting Chen, Yuanyuan Ma, Shuzhen Wei.
       Background: Tumor-associated macrophages (TAMs) are key regulators of immune homeostasis within the tumor microenvironment (TME) and play critical roles in malignant progression. However, the molecular mechanisms linking macrophage metabolic remodeling to immune regulation remain incompletely understood. Glycine cleavage system H protein (GCSH), a core regulator of copper-dependent cell death, has been implicated in metabolic regulation in triple-negative breast cancer (TNBC), suggesting a potential role in macrophage-mediated TME remodeling.
    Methods: We integrated single-cell RNA sequencing and spatial transcriptomic data from TNBC tissues to systematically characterize macrophage subpopulations with high GCSH expression. Pseudotime trajectory analysis, cuproptosis-related scoring, cell-cell communication inference, metabolic pathway enrichment, and spatial localization analyses were performed to delineate their functional heterogeneity and microenvironmental context. In addition, mutation profiling, immunogenomic analysis, drug sensitivity prediction, and in vitro and in vivo functional experiments were conducted to comprehensively evaluate the biological and therapeutic relevance of GCSH.
    Results: GCSH expression was predominantly enriched in macrophages, particularly in early activated subsets, and was associated with enhanced amino acid and lipid metabolic activity. GCSH + macrophages exhibited extensive interactions with T cells via pathways such as MIF-CD74-CXCR4 and LGALS9-CD45, contributing to an immunosuppressive, tumor-promoting microenvironment. Spatial analysis revealed their preferential localization at the tumor core-stroma interface. Notably, GCSH missense mutations were associated with increased M1 macrophage infiltration and enrichment of immune and inflammatory pathways. Clinically, high GCSH expression correlated with poor survival, genomic instability, and chemotherapy resistance. Functional experiments demonstrated that GCSH silencing suppressed tumor cell proliferation, migration, and clonogenicity, induced apoptosis, enhanced proinflammatory cytokine secretion, and significantly inhibited tumor growth in vivo.
    Conclusion: GCSH acts as a central molecular link between macrophage metabolic reprogramming, immune suppression, and TNBC progression, highlighting its potential as both a prognostic biomarker and therapeutic target.
    Keywords:  GCSH; cuproptosis; multiomics; targeted therapy; triple-negative breast cancer
    DOI:  https://doi.org/10.1155/humu/7893655
  13. J Transl Med. 2026 May 12.
    Metabolic pattern changes of macrophages during cancer development and progression.
    Guanfu Liu, Binxue Wang, Shaojie Wang, Shi Li, Hua Han, Tai An.
       BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the immune cell population within the tumor microenvironment (TME), where they play dynamic and multifaceted roles throughout the progression of tumorigenesis. Recent evidence suggests that shifts in macrophage metabolic programs-including glycolysis, oxidative phosphorylation, fatty acid utilization, glutamine metabolism, and the pentose phosphate pathway, are closely associated with diverse and context-dependent functional states rather than fixed polarization phenotypes. During tumor progression toward invasion and metastasis, macrophage metabolic programs dynamically adapt to spatial and temporal variations within the TME, often contributing to immunoregulatory or tumor-supportive niches that facilitate angiogenesis, tumor dissemination, immune evasion, and metabolic crosstalk with tumor cells. However, the precise mechanisms underlying these context-dependent adaptations remain incompletely understood.
    MAIN BODY: This article reviews current evidence regarding TAM activation states and metabolic reprogramming by various signals in the TME during tumorigenesis and tumor progression, as well as dynamic alterations in TAM metabolic patterns. Furthermore, we explore how secondary metabolites present in the TME influence macrophage metabolic reprogramming and summarize current research on potential therapeutic agents targeting macrophage metabolism.
    CONCLUSIONS: We propose that modulating key metabolic regulators in TAMs or intervening in metabolic-immune crosstalk pathways may offer novel strategies for precision medicine in cancer therapy, providing a theoretical foundation for metabolic intervention-based immunotherapeutic approaches.
    Keywords:  Cancer immunotherapy; Immunometabolism; Metabolic intermediates; Metabolic reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s12967-026-08210-1
  14. Int J Mol Sci. 2026 Apr 24. pii: 3790. [Epub ahead of print]27(9):
    Harnessing Cancer Stem Cells and 3D Organoids in Unravelling Spatial and Cellular Heterogeneity in Cancer.
    Eunsong Kwak, Haneul Kim, Eunhye Kim.
      Cancer exhibits pronounced heterogeneity at both spatial and cellular levels, contributing to variability in therapeutic responses and the emergence of treatment resistance. This heterogeneity is underscored by the diverse genetic, epigenetic, and phenotypic variations found within tumor cell populations. Cancer stem cells (CSCs), although representing a minor fraction of tumor cells, possess the capacity to self-renew and differentiate, thereby driving the dynamic evolution of tumor heterogeneity. CSCs interact intricately with various elements of the tumor microenvironment (TME), further amplifying this heterogeneity. Recent advancements in organoid technology have facilitated the development of CSC-derived organoid models that more faithfully recapitulate the TME and intratumoral heterogeneity, which conventional 2D culture systems fail to replicate. These CSC-derived organoid systems not only preserve the structural and genomic characteristics of tumors, but they also enable the exploration and evaluation of therapeutic strategies that reflect tumor complexity. However, CSC-derived organoid systems face several challenges, such as the rarity of CSCs, lack of standardized culture conditions, absence of TME components, limited predictive accuracy, and insufficient modeling of tumor heterogeneity. This review discusses these limitations and explores potential solutions, including the use of artificial intelligence (AI) to enhance treatment predictability. These innovations may improve the utility of organoid models for therapeutic evaluation and for targeting tumor heterogeneity. Ultimately, CSC-derived organoids may serve as a valuable platform for advancing precision medicine and cancer research.
    Keywords:  cancer stem cells (CSCs); organoids; patient-derived organoids (PDOs); tumor heterogeneity; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms27093790
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