bims-ecemfi 2026-02-01 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–02–01
fifteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Mechanical Cues Regulate Estrogen and Progesterone-Induced Nascent ECM Deposition by Human Endometrial Stromal Fibroblasts.
Programming Hydrogel Mechanics via Sequence-Controlled Polymerization Using Peptide Self-Assembly.
Glucose deprivation induces AMPK-dependent α-actinin-4 expression to sustain energy efficient non-proteolytic migration.
A Tunable Coacervate Matrix Emulates Embryonic Extracellular Matrix (ECM) Biophysical Cues To Regulate Stem Cell Fate.
Mechanochemical regulation of organoid morphogenesis: Integrated signaling circuits in engineered microenvironments.
Cancer cell dynamics navigating the complex microenvironment: active nematics and dynamic heterogeneity.
Material-Induced Nuclear Deformation Controls Chromatin Architecture in Adipose Stem Cells.
Density-velocity relation is scale-dependent in epithelial monolayers.
Systematic investigation of the effects of neural stem cell spheroid size and density on fate specification in 3D culture.
A Jagged1-regulated hybrid-EMT state identifies pancreatic cancer stem cells.
How human-derived brain organoids are built differently from brain organoids derived from genetically-close relatives: a multi-scale hypothesis.
Synergizing network topology and solvent compatibility for gels with hyperelasticity and omniadhesion.
Mechanical forces from intercellular peptide self-assembly drive spheroid formation.
Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.
Tumor immune organoids in immunotherapy resistance and drug screening.

J Biomed Mater Res A. 2026 Feb;114(2): e70038

Mechanical Cues Regulate Estrogen and Progesterone-Induced Nascent ECM Deposition by Human Endometrial Stromal Fibroblasts.

Grace K Hinds, Arina Velieva, Joshua Yu-Chung Liu, Avinava Roy, Rima Chavali, Claudia Loebel.

The endometrium, the mucosal lining of the uterus, is a highly regenerative tissue that undergoes cyclic remodeling guided by tightly regulated levels of estrogen and progesterone. Stromal cells, including fibroblasts, are embedded within the connective tissue of the endometrium and contribute to the rapidly changing extracellular matrix (ECM). During the secretory phase, high levels of progesterone induce decidualization of endometrial fibroblasts, which changes their morphology and protein secretion. While it has been shown that the mechanical properties of endometrial tissue, such as the elastic modulus, also contribute to tissue homeostasis and pathology, the interplay between hormones and tissue modulus in contributing to ECM remodeling remains unknown. To address this, we used hydrogels of varying elastic moduli (5 and 15 kPa) to induce decidualization of endometrial fibroblasts. Using metabolic labeling of glycosylated nascent ECM proteins, we then visualized and measured the deposition of newly secreted (nascent) ECM proteins during decidualization. In addition, we designed an automated ImageJ-based workflow for unbiased quantification of nascent ECM deposition. Our results demonstrate that both 5 and 15 kPa hydrogels support decidualization of endometrial stromal fibroblasts as shown by an increase in cell flattening and prolactin secretion. While increased hydrogel modulus alone enhances nascent ECM deposition, decidualization produces an additional increase that converges to similar levels regardless of the initial hydrogel modulus. Collectively, these findings demonstrate that endometrial stromal fibroblasts deposit nascent ECM that is enhanced during decidualization. These observations may provide new insights toward future studies addressing the mechanisms of ECM remodeling in endometrial tissue.

DOI: https://doi.org/10.1002/jbma.70038
J Am Chem Soc. 2026 Jan 29.

Programming Hydrogel Mechanics via Sequence-Controlled Polymerization Using Peptide Self-Assembly.

Abolfazl S Moghaddam, Maahi Zaman, Sz-Chian Liou, E Thomas Pashuck.

Hydrogels often have poor mechanical properties due to their high water content and low polymer concentration, which limits their utility in applications that require them to withstand applied forces. Inspired by natural biopolymers such as collagen and actin, which form highly extended fibrillar networks that stiffen biological tissues, we developed a modular strategy that utilizes self-assembling peptides to direct the formation of covalently polymerized diacetylene networks in hydrogels. By systematically tuning peptide sequences, we precisely controlled the supramolecular organization and molecular orientation within the self-assembled nanofibers. This optimization enabled efficient topotactic polymerization of diacetylene moieties within the self-assembling peptides. Peptide sequences that readily promoted polymerization formed hydrogels with superior viscoelastic properties. Incorporation of these diacetylene peptide amphiphiles (DA-PAs) into covalently cross-linked poly(ethylene glycol) (PEG) hydrogels increased their mechanical stiffness 200-fold, while increasing viscous dissipation over 1,000 times. Modifying the chemical structure of the PEG cross-linker tuned the interfacial interactions between the covalent PEG and DA-PA networks, modulating stiffness by almost an order of magnitude. Since the DA-PAs readily dissolve in water prior to polymerization, they can be incorporated into most hydrogel systems. Adding them to alginate hydrogels led to an almost 20-fold increase in the hydrogel stiffness. This approach, merging peptide-driven supramolecular chemistry with precise covalent polymerization, provides powerful and versatile pathways for fabricating mechanically robust materials that offer new insights into how hierarchical structures can be used to improve hydrogel mechanics.

DOI: https://doi.org/10.1021/jacs.5c12182
J Cell Sci. 2026 Jan 27. pii: jcs.264040. [Epub ahead of print]

Glucose deprivation induces AMPK-dependent α-actinin-4 expression to sustain energy efficient non-proteolytic migration.

Vividha Raunekar, Sumon Kumar Saha, Nikita Sharma, Sarbajeet Dutta, Madhurima Sarkar, Harsha Rani, Neha Deshpande, Shraddha Sansidha Mohanty, Anchita Gopikrishnan, Krithjgnan Bhardhwaj, Sudiksha Mishra, Annapoorni Rangarajan, Ramray Bhat, Vijayalakshmi Mahadevan, Shamik Sen.

  Crosstalk between tumor microenvironmental factors, such as, extracellular matrix (ECM) stiffness and metabolic pathways, regulate cell invasive phenotype in cancer cells. ECM stiffening leads to the collapse of blood vessels leading to oxygen deprivation and nutrient stress. The individual and combined effect of these two factors on the mode of invasion of cancer cells remains poorly understood. Here we show that in breast cancer cells, glucose deprivation induces a switch from an energy demanding proteolytic mode of migration to an energy efficient non-proteolytic mode of migration. Energy demands met by OXPHOS, and nuclear softening sustain this mode of migration. We further show that the energy sensor AMPK mediates this switch through transcriptional activation of the mechanoresponsive actin crosslinking protein α-actinin-4. Collectively, our results demonstrate how AMPK fine-tunes mode of invasion under nutrient constraints by transcriptional activation of α-actinin-4.

Keywords:  ACTN4; AMPK; Energy requirements; Invasion

DOI:  https://doi.org/10.1242/jcs.264040
J Am Chem Soc. 2026 Jan 27.

A Tunable Coacervate Matrix Emulates Embryonic Extracellular Matrix (ECM) Biophysical Cues To Regulate Stem Cell Fate.

Xian Xie, Xu Yan, Rongjie Wu, Zhuo Li, Sien Lin, Liming Bian.

During early embryogenesis, the uterine environment undergoes marked biophysical changes that guide the embryonic cell fate. However, replicating these stage-specific cues in vitro remains challenging. Herein, we introduce a gelatin-based coacervate matrix with phase-transition-mediated tunable mechanics to recapitulate the biophysical cues of pre- and peri-implantation stages. Driven by reversible hydrophobic interactions, liquid-liquid phase separation produces coacervates with ultradynamic structures that enable dramatic volume expansion during cell proliferation in preimplantation stage. Furthermore, the liquid-like coacervate emulates the loosely organized immature extracellular matrix (ECM) of the uterine fluid environment, providing moderate cell-matrix interactions that preserve stemness. Additionally, the coacervate-solution transition allows the efficient harvesting of highly viable embryonic stem cell colonies. Moreover, upon stiffening through the coacervate-hydrogel transition, the matrix promotes peri-implantation-like invasive behaviors, including enhanced cell-matrix adhesion and secretion of ECM-degrading enzymes. These findings establish the biomimetic coacervate matrix as a versatile platform for clonal growth, stemness maintenance, and lineage initiation, offering new opportunities for developmental modeling and therapeutic applications.

DOI: https://doi.org/10.1021/jacs.5c16913
Mater Today Bio. 2026 Apr;37 102782

Mechanochemical regulation of organoid morphogenesis: Integrated signaling circuits in engineered microenvironments.

Xinxin Zhang, Yuanyuan Zhao, Lina Mao, Qiangsong Wang, Pengyu Huang.

  Organoid morphogenesis is orchestrated by complex mechanical interactions between cells and their microenvironment. Recent evidence highlights the critical role of mechanical stimuli-including fluid shear stress, axial tensile and compressive forces, extracellular matrix (ECM) stiffness, and viscoelasticity-in integrating through specialized mechanotransduction hubs to regulate spatial and temporal morphogenetic programs. These mechanical cues are decoded by interconnected signaling architectures, including the MAPK/PI3K-Akt pathways mediating fluidic forces, the Wnt/β-catenin and Hippo-YAP/TAZ cascades responding to axial forces and ECM rigidity, and the integrin-β1-tensin-1-YAP axis interpreting ECM viscoelastic properties. These interconnected networks establish hierarchical control over organoid proliferation, lineage specification, and tissue patterning across diverse culture systems, spanning static elastic substrates to dynamic viscoelastic matrices with tunable stress relaxation profiles. Beyond cytoplasmic signaling, emerging studies identify nuclear mechanotransduction as a central integrative layer that converts mechanical inputs into stable transcriptional and epigenetic outcomes. Mechanical forces transmitted via the cytoskeleton-LINC complex reshape nuclear mechanics through Lamin A-dependent regulation of nuclear stiffness, directly remodel chromatin accessibility, and modulate mechanosensitive transcriptional regulators. Through this nucleus-centred mechanism, transient mechanical cues are encoded as persistent gene expression programmes that govern cell fate specification, tissue layering, and functional compartmentalisation in organoids. This review systematically maps the mechanobiological logic underlying organoid development across three analytical dimensions: molecular decoding of mechanical inputs, cellular-scale integration of mechanotransduction signals, and emergent tissue-level patterning. By elucidating self-reinforcing feedback loops between matrix biophysics, nuclear mechanics, and chromatin organisation, we propose an engineering framework for designing biomimetic microenvironments. This approach enables the development of next-generation organoid platforms with enhanced architectural fidelity and physiological relevance, particularly through spatiotemporal control of viscoelastic memory and dynamic mechanical conditioning.

Keywords:  Cellular microenvironment; Extracellular matrix; Mechanotransduction; Morphogenesis; Nuclear mechanotransduction; Organoid

DOI:  https://doi.org/10.1016/j.mtbio.2026.102782
Soft Matter. 2026 Jan 30.

Cancer cell dynamics navigating the complex microenvironment: active nematics and dynamic heterogeneity.

Trevor Reid, Colton Ramsey, Yang Jiao, Yanping Liu, Bo Sun.

Growing evidence indicates that the motility of multicellular systems exhibits active nematic characteristics. However, the impact of cell-to-cell variability, particularly the relationship between a cell's dynamic phenotype and its contribution to nematic order, remains poorly understood. Here, we examine the motility of monolayers of micropatterned breast cancer cells and observe the emergence of robust nematic order that evolves spatiotemporally, despite the absence of coherent tissue flow. We identify a distinct subpopulation of cells, termed "patrollers", which display strongly polarized migration and appear to reinforce local nematic alignment. To elucidate the underlying mechanisms, we develop a mean-field theoretical model that captures the essential contributions of this subpopulation and yields predictions consistent with our experimental observations. Our results indicate that nematic order within multicellular systems may be driven not by uniform behavior across the entire population, but rather by the dominant influence of a specialized subset of cells that orchestrate collective alignment.

DOI: https://doi.org/10.1039/d5sm01210d
Adv Sci (Weinh). 2026 Jan 30. e14458

Material-Induced Nuclear Deformation Controls Chromatin Architecture in Adipose Stem Cells.

Carlo F Natale, Luca Messina, Valeria Panzetta, Stefania Saporito, Costantino Menna, Maurizio Ventre, Paolo A Netti.

  The 3D organization of the nucleus is crucial for maintaining cellular homeostasis and function, and it is dynamically regulated by both internal and external forces. Here, we investigate how material-induced cell deformation-generated by engineered micropatterned substrates-influences nuclear morphology and chromatin condensation in adipose-derived stem cells (ASCs). Using a multiscale approach that integrates mechanical modeling, atomic force microscopy (AFM), confocal imaging, and high-resolution analysis, we show that the surface micropatterning modulates intracellular force distributions, which in turn reshape the nuclear envelope and alter chromatin organization. Finite Element simulations reveal that distinct deformation profiles lead to region-specific mechanical stress across the nuclear envelope. These mechanical cues correlate with local chromatin decondensation, as demonstrated by 3D chromatin reconstructions and quantitative morphometric analyses. Our findings demonstrate that cell mechanical perturbations imposed by single-cell micropatterning can shape chromatin architecture and chromosome inter-distances. This opens new avenues for understanding mechanogenomic regulation and designing biomaterials that harness physical cues to control cell behavior.

Keywords:  actin cytoskeleton; cell mechanics; heterochromatin; nucleus deformation

DOI:  https://doi.org/10.1002/advs.202514458
Soft Matter. 2026 Jan 27.

Density-velocity relation is scale-dependent in epithelial monolayers.

Hengdong Lu, Tianxiang Ma, Amin Doostmohammadi.

The relationship between cell density and velocity is often assumed to be negative, reflecting crowding-induced suppression of movement. However, observations across systems reveal a more nuanced picture: while some emphasize contact inhibition of locomotion, others suggest that dense regions exhibit enhanced activity due to force generation. Here, using experimental measurements we show that density-velocity relation in epithelial monolayers is inherently scale dependent. By coarse-graining cell motion over multiple spatial windows, we find that cell velocity magnitude correlates positively with local density at small scales, but negatively at large scales. Employing traction force measurements, we find that this crossover coincides with the emergence of mechanical pressure segregation, defining a characteristic length scale beyond which crowding dominates. A minimal model incorporating activity-induced shape changes reproduces this crossover and identifies the competition between active force generation and mechanical confinement as the underlying mechanism. Our results reconcile conflicting views of density-regulated migration and highlight an emergent length scale as a key factor in interpreting collective cell dynamics.

DOI: https://doi.org/10.1039/d5sm01054c
J Mater Chem B. 2026 Jan 27.

Systematic investigation of the effects of neural stem cell spheroid size and density on fate specification in 3D culture.

Rebecca Duquette, Sabrina Pietrosemoli Salazar, Ze Zhong Wang, Alireza Sohrabi, Stephanie K Seidlits.

A systematic understanding of how the density of neural stem/progenitor cells (NS/PCs) embedded within three-dimensional (3D) biomaterials affect cell behavior will be necessary for developing effective strategies to generate CNS tissues. Here, we investigated the effects of local and global cell density of mouse neural stem cells (mNSCs) on their viability, proliferation, and differentiation when cultured in 3D, hyaluronic acid (HA)-based hydrogel matrices. Specifically, we assessed the influence of spheroid size, which represents local cell density, (small: 100 cells per sphere, large: 200 cells per sphere) and seeding density (low: 100 000 cells per hydrogel, high: 200 000 cells per hydrogel), which represents global density, on cellular outcomes. Results reveal that these factors have both independent and interactive effects on NS/PC viability and fate. Cultures of smaller spheres at low global densities yield more glial cells, including astrocytes and oligodendrocytes. In contrast, cultures with high global densities, regardless of sphere size, better preserved stem-like mNSC phenotypes. Strikingly, cultures with 1000 total spheres per hydrogel, regardless of sphere size or overall cell concentration, best maintained viability while promoting neuronal maturation. These findings highlight the importance of controlling both local and global cell densities in 3D cultures to achieve reproducible mNSC-derived populations for use as in vitro test beds or biomanufacturing of therapeutic stem cells.

DOI: https://doi.org/10.1039/d5tb01589h
Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01681-X. [Epub ahead of print]45(2): 116909

A Jagged1-regulated hybrid-EMT state identifies pancreatic cancer stem cells.

Linxiang Lan, Huafu Li, Shiwei Zhang, Cristina Maria Garrone, Yonglin Wu, May Zaw Thin, Yihang Pan, Changhua Zhang, Yulong He, Rocio Sancho, Axel Behrens.

  Pancreatic ductal adenocarcinoma (PDAC) shows great cellular heterogeneity, with pronounced epithelial and mesenchymal cancer cell populations. We previously identified a PDAC subpopulation, marked by the tetraspanin CD9, which is capable of initiating PDAC and giving rise to PDAC heterogeneity. Here, we characterize a subset of CD9-high (CD9hi) tumor-initiating cells (TICs) with hybrid epithelial-mesenchymal transition (EMT) features, which show increased cancer stem cell properties, as evidenced by increased capacity to form organoids and generate epithelial and mesenchymal tumor cell progeny. Depletion of hybrid-EMT CD9hi cells leads to a gradual collapse of organoid formation and tumorigenic capability, suggesting that CD9hi TICs are required for long-term organoid formation and tumorigenicity. Hybrid-EMT CD9hi TICs upregulate the Notch ligand Jagged1, and Jag1 depletion or Notch inhibition impairs TIC self-renewal and PDAC cell differentiation. Conversely, Jag1 overexpression augments TIC self-renewal. Thus, Jagged1-mediated Notch signaling controls a hybrid-EMT state that is a defining feature of TICs in PDAC.

Keywords:  CD9; CP: cancer; CP: cell biology; Jagged1; Notch; hybrid epithelial-mesenchymal transition

DOI:  https://doi.org/10.1016/j.celrep.2025.116909
Soft Matter. 2026 Jan 26.

How human-derived brain organoids are built differently from brain organoids derived from genetically-close relatives: a multi-scale hypothesis.

Tao Zhang, Sarthak Gupta, Madeline A Lancaster, J M Schwarz.

How genes influence tissue-scale organization remains a longstanding biological puzzle. While experimental efforts quantify gene expression, chromatin, cellular, and tissue structure, computational models lag behind. To help accelerate multiscale modeling, we demonstrate how a tissue-scale, cellular-based model can be merged with a cell nuclear model incorporating a deformable lamina shell and chromatin to test hypotheses linking chromatin and tissue scales. Specifically, we propose a hypothesis to explain structural differences between human, chimpanzee, and gorilla-derived brain organoids. Recent experiments reveal that a cell fate transition from neuroepithelial to radial glial cells includes a new intermediate state that is delayed in human-derived organoids, leading to significantly narrowed and lengthened apical cells. Additional experiments also demonstrated that ZEB2, a transcription factor, plays a major role in the onset of the novel intermediate state. We hypothesize that this delay stems from chromatin reorganization triggered by mechanical strain as the respective brain organoids develop, with a higher critical threshold in human-derived cells. Here, we computationally test the feasibility of such a hypothesis by exploring how slightly different initial configurations of chromatin, as modeled by different numbers of chromatin crosslinkers, organize in response to mechanical strain with increasingly different initial configurations representing less genetically-close relatives. We find that even small differences in the number of chromatin crosslinkers (>0.01%) yield distinguishable chromatin displacement on average beyond 35% mechanical strain. At higher strains, we observe a new type of nonlinear chromatin scaling law with an exponent of 3.24(5). Finally, we show how differences in chromatin strain maps and more conventional contact maps can reveal structural distinctions between genetically-close species.

DOI: https://doi.org/10.1039/d5sm01116g
Sci Adv. 2026 Jan 30. 12(5): eaec7718

Synergizing network topology and solvent compatibility for gels with hyperelasticity and omniadhesion.

Qiqi Xue, Xinyu He, Jincheng Lei, Wei Hong, Canhui Yang.

In polymeric gels, hyperelasticity and strong adhesion are often required but difficult to achieve simultaneously. Here we propose a principle of hyperelastic and omniadhesive gels composed of polymer networks with long dangling chains and sufficient good solvents. The molecules of good solvents screen off interchain interactions for hyperelasticity. The long dangling chains disentangle and adsorb to substrate for strong adhesion. We synthesized such gels by controlling the polymerization kinetics. When a monomer solution is partially cured, some monomers form a network and others form the solvent. The resulting gel, termed homogel, consists of a polymer network with enormous dangling chains and solvent of identical chemistries. An interval exists where the dangling chains are long and disentangled substantially, and the homogel exhibits both hyperelasticity and omniadhesion. We demonstrated such a gel with a hysteresis of 4.1% (stretch = 10) and adhesion energy of ~510 joules per square meter. The principle is generic and applicable to gels of different types.

DOI: https://doi.org/10.1126/sciadv.aec7718
Nat Commun. 2026 Jan 26.

Mechanical forces from intercellular peptide self-assembly drive spheroid formation.

Honglei Lu, Yaoting Li, Xuejiao Yang, Bihan Wu, Deling Kong, Chen Li, Huaimin Wang, Zhaoqianqi Feng.

This work presents a general strategy for engineering cell spheroids with capillary-like structures using intercellular self-assembly of peptide nanofibers. These nanofibrous materials induce mechanical changes in the extracellular matrix (ECM), activate mechanotransduction pathways, and enhance cellular morphogenesis, resulting in dynamic 3D spheroids with improved cell-cell and cell-matrix interactions. By promoting the formation of capillary-like structures within tumor spheroids, we develop models that closely mimic human tissue physiology. Our results demonstrate that tumor spheroids with capillary-like structures display gene expression profiles that closely match those of patient-derived tumors, underscoring their relevance for cancer research. Furthermore, these spheroids, including those derived from an islet cell line, exhibit significantly increased functionality, such as enhanced insulin secretion in response to glucose stimulation, highlighting their potential for diabetes research and regenerative medicine applications. This work advances our understanding of tissue engineering and provides a robust platform for studying complex cellular interactions and therapeutic responses. By highlighting the critical role of capillary-like structure formation in engineered tissues, our findings pave the way for innovative strategies to address significant challenges in drug delivery and cancer therapy, ultimately enhancing patient care and treatment outcomes.

DOI: https://doi.org/10.1038/s41467-026-68513-1
Elife. 2026 Jan 29. pii: RP103550. [Epub ahead of print]14

Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.

Yue Lu, Tezin Walji, Pratima Pandey, Chuanli Zhou, Christa W Habela, Scott B Snapper, Rong Li, Elizabeth H Chen.

  Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. Fusion of satellite cell-derived myoblasts (SCMs) is indispensable for generating the multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain incompletely understood. Here, we reveal a critical role for branched actin polymerization in SCM fusion during mouse skeletal muscle regeneration. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors N-WASP and WAVE, we demonstrate that branched actin polymerization is specifically required for SCM fusion but dispensable for satellite cell proliferation, differentiation, and migration. We show that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion and that branched actin polymerization is essential for generating invasive protrusions at fusogenic synapses in SCMs. Together, our study identifies branched-actin regulators as key components of the myoblast fusion machinery and establishes invasive protrusion formation as a critical mechanism enabling myoblast fusion during skeletal muscle regeneration.

Keywords:  Arp2/3 complex; branched actin polymerization; developmental biology; invasive protrusions; mouse; myoblast fusion; regenerative medicine; satellite cells; skeletal muscle regeneration; stem cells

DOI:  https://doi.org/10.7554/eLife.103550
Drug Resist Updat. 2026 Jan 23. pii: S1368-7646(26)00011-7. [Epub ahead of print]85 101360

Tumor immune organoids in immunotherapy resistance and drug screening.

Minghui Zhang, Lijun Li, Haihong Pu, Yan Wang, Xiaoxin Zhang, Xiaotian Guo, Yanbin Zhao, Qingwei Meng, Mingzhu Yin.

  Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.

Keywords:  Immunotherapy; Personalized treatment; Resistance; Tumor immune organoids; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2026.101360