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Abstract
T-cell immunotherapy has progressed rapidly, evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer. This review explores engineering strategies, ranging from natural TCRs to synthetic receptors, that increase T-cell activation and therapeutic potential. We begin by highlighting the foundational role of native receptors in the T-cell response, emphasizing how these structural and functional insights inform the design of next-generation synthetic receptors. Comparisons between CAR and TCR-like synthetic receptors underscore their respective advantages in specificity, efficacy, and safety, as well as potential areas for further improvement. In addition, gene editing technologies such as CRISPR-Cas9 enable precise modifications to the T-cell genome, enhancing receptor performance and minimizing immunogenic risks. In addition to tumors, these engineered T cells can be directed against viral infections, autoimmune disorders, and other diseases. We also explore advanced strategies that engage multiple immune cell types to achieve synergistic, durable responses. By demonstrating how native and synthetic receptors collectively drive innovation, this review aims to inspire new research directions and ultimately expand the scope of T-cell engineering for universal therapeutic applications.
Highlights
T cells play a pivotal role in defending against infection and cancer
chimeric antigen receptor (CAR)-Ps consist of an antibody fragment that targets specific antigens, enhancing macrophage phagocytosis. These findings demonstrate that CARs for phagocytosis (CAR-Ps)-expressing macrophages can effectively engulf antigen-coated particles and reduce cancer cell numbers by more than 40% in coculture [240]
The levels of inflammatory cytokines such as TNF-α and IL-6 are significantly lower in the blood of treated mice, suggesting a reduced risk of cytokine release syndrome (CRS) [242]. These findings indicate that targeting the extracellular matrix (ECM) with engineered macrophages could be an effective strategy for treating solid tumors, promoting T-cell activity while minimizing side effects
Summary
The highly specific recognition of pathogens and tumor cells is mediated by the T-cell receptor (TCR), which undergoes somatic rearrangement and mutation to achieve vast antigen diversity. First-, second- and thirdgeneration CARs replace the extracellular domain with a singlechain variable fragment (scFv) specific to tumor antigens, while their cytoplasmic domain comprises the ζ chain and one (second generation) or two (third generation) costimulatory receptors, such as 4-1BB or CD28 [5–9]. CAR-T-cell therapy shows limited efficacy in solid tumors, possibly due to early T-cell exhaustion prior to tumor infiltration. These findings indicate the need for further CAR optimization to meet the requirements of treating solid tumors [10]
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