Investigating the dynamic interactions between CAR-T cells and the tumor microenvironment: intelligent regulation strategies

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated significant success in treating hematological malignancies; however, its effectiveness is often constrained by the immunosuppressive network within the tumor microenvironment (TME). The interactions between CAR-T cells and the TME are complex and variable, and the regulatory mechanisms underlying these interactions are reviewed here. This review highlights the effect of TME heterogeneity on therapeutic outcomes and offers a comprehensive framework for understanding the dynamic evolution of the TME at high resolution by integrating insights from single-cell multi-omics and spatial omics technologies. This review also focuses on intervention strategies, including nanotechnology-based delivery systems, metabolic reprogramming, and genetic engineering, that enable active modulation of the TME. A conceptual shift from passive resistance to programmable regulation is proposed, in which CAR-T cells and their carriers are engineered to sense cues from the TME and respond through conditional, intelligent regulatory circuits that remodel the TME. This review combines mechanistic insights with translational strategies, offering a cohesive perspective on overcoming resistance and improving the efficacy, safety, and durability of CAR-T therapies. These advancements are expected to accelerate the development of precision immunotherapy for malignant tumors.