Biomaterial-driven 3D scaffolds for immune cell expansion toward personalized immunotherapy.

Immunotherapy has emerged as a transformative medical approach in recent years, providing novel treatments for cancer eradication, autoimmune disorders, and infectious diseases. Fundamental to the success of therapy is the enrichment of the immune cell population, particularly T cells, natural killer cells, and dendritic cells. However, achieving a robust and long-term proliferation of immune cells is still challenging both in vivo and ex vivo. In vivo expansion leverages the patient's natural microenvironment and regulatory mechanisms through therapeutic interventions like immune checkpoint inhibitors, cytokine therapy, and targeted antibodies. This approach fosters long-term immune memory and sustained protection. In contrast, ex vivo expansion involves isolation, manipulation, and expansion of the immune cells under controlled conditions before reinfusion, allowing for precise control over the process and generating potent immune cell populations. Hydrogels, due to their tunable biomechanical properties, high biocompatibility, and ability to mimic the extracellular matrix, provide an ideal platform for both in vivo and ex vivo immune cell expansion. For instance, hydrogel-based scaffolds or beads can facilitate a controlled and efficient expansion of immune cells ex vivo, whereas injectable and implantable hydrogels can provide innovative solutions for enhancing immune cell activity within the patient supporting prolonged immune cell activity. This review aims to elucidate the importance of hydrogel-based strategies in immune cell expansion, advancing the development of effective, personalized immunotherapies to improve patient outcomes. STATEMENT OF SIGNIFICANCE: This review highlights the transformative potential of hydrogel-based 3D scaffolds in advancing personalized immunotherapy. By integrating in vivo and ex vivo strategies, hydrogels provide an innovative platform to enhance immune cell expansion, addressing critical challenges in immunotherapy. The discussion emphasizes the unique biomechanical and biochemical tunability of hydrogels, enabling precise mimicry of the extracellular matrix to support T cell proliferation, activation, and memory formation. These advances offer scalable, cost-effective solutions for producing high-quality immune cells, contributing to more effective cancer treatments, autoimmune disease management, and infectious disease control. By bridging materials science and immunology, this work underscores the pivotal role of hydrogels in shaping the future of immune-based therapies.