Advancing CAR-Engineered Cell Therapies: Pharmacological Mechanisms of Efficacy, Persistence, and Safety

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed cancer immunotherapy, achieving remarkable clinical responses, particularly in hematological malignancies. However, several challenges continue to limit its broader and durable therapeutic success. These limitations include antigen escape and heterogeneity, insufficient CAR-T cell persistence, T-cell exhaustion, limited trafficking and activity in solid tumors, and an immunosuppressive tumor microenvironment. Treatment-associated toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target/off-tumor effects, further emphasize the need to improve therapeutic control. Advances in CAR structure and function, cellular signaling, antigen recognition, safety-control strategies, and emerging approaches for generating CAR-T cells provide new opportunities to enhance efficacy while reducing toxicity. Moreover, CAR-based therapy is expanding beyond conventional T cells to include CAR-engineered NK cells, macrophages, dendritic cells, neutrophils, and other immune-cell populations, creating new opportunities to improve therapeutic efficacy, persistence, and safety across cancer and emerging non-malignant indications.This Research Topic aims to build a pharmacology-first, mechanism-driven understanding of how CAR-engineered cell therapies achieve efficacy, persistence, and safety. A central objective is to define the drug–target pharmacology of CAR constructs — antigen binding and affinity thresholds, signalling-domain pharmacodynamics, and the dose–exposure–response relationships that govern activation, cellular function, and durability. Building on this framework, the collection will examine how receptor characteristics, costimulatory and intracellular signalling, cellular phenotype, metabolic fitness, and interactions with the tumor microenvironment shape therapeutic outcomes. Particular attention will be given to advances that optimize target recognition, overcome antigen escape, therapeutic resistance, and disease-associated immunosuppression, and improve the selectivity and controllability of CAR-based therapies while reducing treatment-related toxicities. A distinctive focus is the expansion of CAR engineering across multiple effector platforms — CAR-NK cells, macrophages, and dendritic cells alongside CAR-T cells — together with emerging strategies for the direct in situ / in vivo generation of CAR-engineered cells, where these offer opportunities to improve therapeutic outcomes, durability, accessibility, or safety.This Research Topic welcomes pharmacology- and mechanism-focused contributions on the efficacy, persistence, and safety of CAR-engineered cell therapies. Priority areas include the drug–target pharmacology of CAR constructs — receptor binding and affinity thresholds, signalling-domain pharmacodynamics, and dose–exposure–response relationships; CAR structure and signalling; costimulatory and intracellular signalling domains; cellular fitness, metabolism, and persistence; antigen escape and therapeutic resistance; the tumor microenvironment and barriers in solid tumors; multi-targeted, armored, switchable, inducible, and logic-gated CAR designs; strategies to improve safety and controllability; and biomarkers of response and toxicity. As a distinctive core, we especially encourage work spanning multiple CAR platforms — CAR-NK cells, macrophages, dendritic cells, neutrophils, and other emerging cellular platforms alongside CAR-T cells — and approaches for the in situ / in vivo generation of CAR-engineered cells. Translational and pharmacological studies that connect CAR characteristics and cellular function with therapeutic efficacy and safety are particularly encouraged.We welcome Original Research, Reviews, Systematic Reviews, Mini Reviews, Perspectives, Methods, and Hypothesis and Theory articles relevant to these themes. Topic editors: Alka Dwivedi, Taisuke Kondo, Hannah Song Source: https://www.frontiersin.org/research-topics/85532/advancing-car-engineered-cell-therapies-pharmacological-mechanisms-of-efficacy-persistence-and-safety