Integrated Engineering of CAR‐T Cells for Solid Tumours
TL;DR
This review examines the transition from single‐axis engineering to an integrated framework that addresses hurdles in sequence, and delineates how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion.
Abstract
Chimeric antigen receptor (CAR) T‐cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T‐cell dysfunction. This review examines the transition from single‐axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion. We also assess strategies that actively reshape the immunosuppressive TME, including depletion of regulatory cell populations, blockade of ‘don't eat me’ signals, and the use of biomaterial scaffolds for locoregional delivery. The synthesis of controllable activation, intrinsic resilience, and extrinsic TME modulation is defining a class of adaptive therapeutic systems. Clinical implementation of this approach requires careful management of toxicities, notably cytokine release syndrome (CRS), and support from advanced monitoring technologies. Progress will depend on rational combinations that move beyond isolated optimisations, enabling cellular therapies to dynamically respond to evolving tumour ecosystems and narrowing the efficacy gap between hematologic and solid cancers.