Microfluidic perspectives on chimeric antigen receptor T-cell migration in solid tumours: highlighting physical confinement as a key barrier.

Abstract

Chimeric antigen receptor (CAR) T-cell migration and infiltration into solid tumours remains a central challenge for cancer immunotherapy. While factors such as chemokine gradients, extracellular matrix (ECM) stiffness, and immunosuppressive signalling have been well-documented, the physical confinement imposed by tumour architecture is increasingly recognized as a critical barrier. Tumour-associated ECM remodelling generates micro- and nano-scale geometric constraints that significantly alter how immune cells, particularly CAR T-cells, navigate the tumour microenvironment (TME). This article argues that physical confinement merits to be positioned at the centre of the migration challenge, not as an accessory to chemical or biochemical cues. Sustained from both fundamental cell migration biology and recent engineering advances, we highlight how designing microfluidic devices with defined geometric features can uniquely capture the role of confinement in immune cell behaviour and model this challenge. By enabling precise design control over pore size, channel geometry, and nature-inspired structures, these platforms will allow researchers to decouple confinement from other overlapping variables such as stiffness.