Cancer immunotherapy has transformed oncology by enabling targeted activation of antitumor immune responses in patients with relapsed or refractory malignancies. Among adoptive cell transfer (ACT) strategies, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a pivotal therapeutic advancement, genetically redirecting T lymphocytes to recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation. This review provides a comprehensive overview of the biological principles, design evolution, manufacturing platforms, clinical applications, resistance mechanisms, toxicities, and future directions of CAR-T cell therapy within cancer immunotherapy. Specifically, we examine the evolution of CAR architecture, spanning from first-generation constructs to advanced armored and fifth-generation platforms. Furthermore, we compare viral and non-viral gene delivery systems and discuss emerging approaches such as in vivo CAR engineering, allogeneic "off-the-shelf" products, logic-gated receptors, safety switches, and alternative immune-cell platforms, including natural killer (NK) cells and macrophages. CAR-T cell therapy has achieved its most profound clinical success in hematological malignancies, particularly in cluster of differentiation 19 (CD19)-positive B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma, reporting durable remission rates of approximately 60-90% in specific clinical contexts. However, broader clinical translation, particularly in solid tumors, remains constrained by challenges such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), antigen escape, tumor heterogeneity, poor trafficking, limited persistence, high manufacturing costs, and the immunosuppressive tumor microenvironment (TME). While next-generation strategies-including clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated editing, lipid nanoparticle (LNP)-based messenger ribonucleic acid (mRNA) delivery, bispecific CARs, and inducible suicide switches-hold promise for improving safety, specificity, scalability, and accessibility, a significant number remain in preclinical or early-phase clinical development. Overall, CAR-T cell therapy represents a transformative "living drug" platform in oncology; however, its broader clinical utility is contingent upon improving durability, reducing toxicity, overcoming solid-tumor barriers, and validating next-generation technologies through robust, long-term clinical studies.
Bedada et al. (2026) studied this question.