Engineered immune cells and extracellular vesicles target tumour microenvironment barriers in solid tumour...

Adoptive cell therapy (ACT) for solid tumours frequently fails because the tumour microenvironment (TME) imposes multiple, overlapping barriers, including stromal exclusion, suppressive myeloid networks, inhibitory cytokines and metabolites, and antigen heterogeneity. Collectively, these factors markedly restrict the infiltration, persistence, and cytotoxic function of effector lymphocytes. In this Review, we synthesise recent primary studies, consensus guidance, and clinical-trial evidence on engineered-cell therapies, including chimeric antigen receptor (CAR) T cells, T-cell receptor-engineered T cells (TCR-T cells), CAR-NK cells, CAR-macrophages (CAR-M), and emerging in vivo CAR-engineering strategies, together with extracellular-vesicle (EV)-based therapeutics. We then map each platform to mechanism-linked resistance nodes within the TME. For engineered cells, key design levers include context-restricted recognition to reduce on-target/off-tumour toxicity, resistance to dominant suppressive pathways such as TGF-β and adenosine signalling, improved trafficking and tissue penetration, and controllability through transient programming or pharmacological switches. For EVs, the main translational advantages include tissue penetration, modular surface engineering, cargo loading, and their acellular nature, which avoids risks related to in vivo cellular expansion but introduces distinct challenges such as rapid clearance, immunogenicity, batch heterogeneity, and uncertain potency assays. Early clinical data using KRAS G12D-targeting engineered exosomes in metastatic pancreatic cancer support the feasibility of this approach and suggest that EVs may also remodel the immune microenvironment, providing a rationale for combination strategies. We propose a barrier-matched framework in which engineered cells and extracellular vesicles are assigned as functionally orthogonal but complementary modules: engineered cells provide adaptive cytotoxicity, whereas EVs enable microenvironmental reconditioning. This framework may help guide rational combination strategies designed to systematically dismantle resistance in solid tumours.