Rewiring the Tumor-Immune Ecosystem: Extracellular Vesicles in the Next Era of Cancer Immunotherapy.

Abstract

Cancer immunotherapy has transformed oncology by enabling immune-mediated tumor elimination; however, durable responses remain limited, particularly in solid tumors due to antigen heterogeneity, immunosuppressive tumor microenvironment, and adaptive resistance mechanisms. To overcome these barriers, therapeutic paradigms are expanding from single-agent interventions toward programmable cellular and acellular platforms. This review examines recent advances in CAR-T, CAR-NK, and TCR-engineered cell therapies alongside key resistance mechanisms. In parallel, we evaluate the dual biological role of extracellular vesicles (EVs) as mediators of immune evasion and as engineered delivery tools. Rather than presenting multimodal integration as an inherently superior solution, we critically evaluate the trade-offs of combining engineered cells, EVs, checkpoint blockade, oncolytic viruses, and targeted agents, focusing on therapeutic synergy versus cumulative toxicity and biomanufacturing complexity. Collectively, we propose that future cancer immunotherapy will rely on multi-modal, adaptive, and systems-level engineering approaches capable of dynamically reshaping the tumor-immune ecosystem to achieve sustained tumor regression and durable overall survival.