A thermo-responsive collapse system for controlling heterogeneous cell localization, ratio and interaction for three-dimensional solid tumor modeling
Abstract
Cancer immunotherapy using engineered cytotoxic effector cells has demonstrated significant potential. The limited spatial complexity and controllability of existing in vitro models, however, pose a challenge to mechanistic studies attempting to improve existing approaches of effector cell-mediated cytotoxicity within a three-dimensional (3D), solid tumor-like environment. To gain additional experimental control, we developed an approach for constructing 3D culture models using smart polymers that form temperature responsive hydrogels. By embedding cells within hydrogel compartments and exploiting a thermally induced phase transition, multiple cell populations could be assembled at defined ratios on-demand and gently repositioned in space. These systems were amenable to imaging at low- and high-resolution to evaluate cell-to-cell interactions, as well as to dissociation to allow for single cell analyses. We have called this approach “thermal collapse of strata” (TheCOS) and demonstrated its use in creating complex cell assemblies on demand in both layered and spheroidal formats. We then applied TheCOS to investigate how the directionality of natural killer (NK) cell degranulation shapes cytotoxicity in 3D. Dynein inhibition, which disrupts lytic granule convergence and polarization, has previously been shown to promote bystander killing in cell suspensions. Using TheCOS, we showed that lytic granule dispersion induced by dynein inhibition can be sustained in 3D and results in a multi-directional killing including that of non-triggering bystander cells. By imaging TheCOS experiments, we were able to map a “kill zone” associated with multi-directional degranulation in simulated solid tumor environments. TheCOS should allow for the testing of approaches to alter the mechanics of cytotoxicity as well as to generate a wide array of human tumor microenvironments to assist in the acceleration of tumor immunotherapy.
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BibTeX
@article{li2026thermoresponsive,
title = {{A thermo-responsive collapse system for controlling heterogeneous cell localization, ratio and interaction for three-dimensional solid tumor modeling}},
author = {Yu Li and Jordan S. Orange},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73116-3},
url = {https://www.nature.com/articles/s41598-026-73116-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A thermo-responsive collapse system for controlling heterogeneous cell localization, ratio and interaction for three-dimensional solid tumor modeling
AU - Yu Li
AU - Jordan S. Orange
PY - 2026
DA - 2026/10/19
JO - Scientific Reports
DO - 10.1038/s41598-026-73116-3
UR - https://www.nature.com/articles/s41598-026-73116-3
AB - Cancer immunotherapy using engineered cytotoxic effector cells has demonstrated significant potential. The limited spatial complexity and controllability of existing in vitro models, however, pose a challenge to mechanistic studies attempting to improve existing approaches of effector cell-mediated cytotoxicity within a three-dimensional (3D), solid tumor-like environment. To gain additional experimental control, we developed an approach for constructing 3D culture models using smart polymers that form temperature responsive hydrogels. By embedding cells within hydrogel compartments and exploiting a thermally induced phase transition, multiple cell populations could be assembled at defined ratios on-demand and gently repositioned in space. These systems were amenable to imaging at low- and high-resolution to evaluate cell-to-cell interactions, as well as to dissociation to allow for single cell analyses. We have called this approach “thermal collapse of strata” (TheCOS) and demonstrated its use in creating complex cell assemblies on demand in both layered and spheroidal formats. We then applied TheCOS to investigate how the directionality of natural killer (NK) cell degranulation shapes cytotoxicity in 3D. Dynein inhibition, which disrupts lytic granule convergence and polarization, has previously been shown to promote bystander killing in cell suspensions. Using TheCOS, we showed that lytic granule dispersion induced by dynein inhibition can be sustained in 3D and results in a multi-directional killing including that of non-triggering bystander cells. By imaging TheCOS experiments, we were able to map a “kill zone” associated with multi-directional degranulation in simulated solid tumor environments. TheCOS should allow for the testing of approaches to alter the mechanics of cytotoxicity as well as to generate a wide array of human tumor microenvironments to assist in the acceleration of tumor immunotherapy.
SN - 2045-2322
ER -