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Updated: Apr 12, 2026
Analysis of Cancer Cell Invasion and Anti-metastatic Drug Screening Using Hydrogel Micro-chamber Array HMCA-based Plates
Published on: October 25, 2018
Smart hydrogels for overcoming cancer multidrug resistance
Yong Wang1,2, Baoyan Liu3, Zou-Fang Huang4
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, 11439, USA.
Abstract:
Multidrug resistance (MDR) remains the principal impediment to curative oncology, driven by complex interplays between cancer cells and the tumor microenvironment (TME). While nanomedicines have sought to overcome these delivery barriers, their clinical translation is often hampered by the heterogeneity of the enhanced permeability and retention (EPR) effect and by inefficient intratumoral delivery. In this review, we argue that overcoming MDR requires a transition beyond traditional passive drug delivery, advocating active, localized remodeling of the tumor ecosystem. Next-generation injectable hydrogels are increasingly recognized as localized viscoelastic niches that combine controlled intratumoral retention with the capacity to actively modulate biological responses within tumor TME. By converging principles of mechanobiology and immunometabolism, these hydrogels enable a multi-tiered strategy to dismantle multidimensional MDR. This approach begins with the biomechanical softening of the extracellular matrix to decouple mechanotransduction driven by Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), followed by the metabolic disruption of hypoxia-driven bioenergetics. Beyond the extracellular landscape, nanogel-enabled trafficking allows payloads to circumvent intracellular sequestration and efflux transporters, while immunomodulatory niches mobilize antitumor immunity through in situ vaccination and myeloid reprogramming. Finally, we evaluate the integration of artificial intelligence-driven design and patient-derived organoids as a technical bridge to reconcile laboratory ingenuity with clinical utility, aiming to transform the TME into a vulnerable therapeutic target.
Insights
Multidrug resistance in cancer can be overcome by actively remodeling the tumor microenvironment. Injectable hydrogels can soften the tumor matrix and disrupt cancer cell metabolism for improved drug delivery and immune response.
Area of Science:
- Oncology
- Nanomedicine
- Biomaterials
Background:
- Multidrug resistance (MDR) is a major obstacle in cancer treatment.
- Current nanomedicines face challenges with tumor microenvironment (TME) delivery and heterogeneity.
- Passive drug delivery strategies are insufficient for overcoming MDR.
Purpose of the Study:
- To review strategies for overcoming MDR by active TME remodeling.
- To highlight the potential of next-generation injectable hydrogels in cancer therapy.
- To explore the integration of mechanobiology, immunometabolism, and AI for enhanced oncology treatments.
Main Methods:
- Utilizing injectable hydrogels for localized TME modulation.
- Applying principles of mechanobiology to soften the extracellular matrix and decouple YAP/TAZ signaling.
- Disrupting tumor hypoxia-driven bioenergetics and enhancing drug delivery.
- Leveraging nanogel trafficking to bypass intracellular drug sequestration and efflux pumps.
- Mobilizing antitumor immunity via in situ vaccination and myeloid cell reprogramming.
- Integrating artificial intelligence (AI) and patient-derived organoids for treatment optimization.
Main Results:
- Hydrogels can create viscoelastic niches for controlled drug retention and TME modulation.
- Biomechanical softening of the TME disrupts YAP/TAZ-mediated mechanotransduction.
- Metabolic disruption targets hypoxia-driven cancer cell bioenergetics.
- Nanogel systems facilitate payload delivery, overcoming intracellular resistance mechanisms.
- Immune cell reprogramming and in situ vaccination enhance antitumor responses.
- AI and organoid models offer a pathway for clinical translation.
Conclusions:
- Active, localized TME remodeling using advanced hydrogels offers a promising strategy against MDR.
- This multi-tiered approach integrates biomechanics, immunometabolism, and nanomedicine for synergistic effects.
- AI and patient-derived organoids are crucial for bridging laboratory research and clinical application in oncology.
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