Nanosystem-Mediated Intercellular Crosstalk Modulation in the Tumor Microenvironment for Enhanced Cancer Immunotherapy.

Intercellular crosstalk in the tumor microenvironment (TME) is a central determinant of cancer progression and therapy response, in which malignant, immune, stromal and vascular compartments exchange information mainly through extracellular vesicles, signaling pathways, and metabolic cues. These communication circuits can enforce immune exclusion, sustain immunosuppressive cell states and enable adaptive resistance, thereby limiting the durability of otherwise effective therapies. Nanosystems have emerged as enabling tools to modulate this crosstalk across major tumor-centered interaction axes, including tumor cell-immune, tumor cell-stromal, and tumor cell-endothelial interactions, because their tunable physicochemical properties can support context-matched delivery, coordinated co-delivery and controlled exposure profiles that together facilitate multi-node intervention while aiming to reduce off-target perturbation. In this Review, we synthesize key mechanisms of intercellular crosstalk in the TME and summarize nanosystem strategies to reprogram these communication circuits for improved therapy, while outlining translational priorities including causal validation and regimen optimization. Collectively, nanosystem-mediated crosstalk modulation provides a unifying framework that may help shift the TME from a therapy-resistant ecosystem toward a more therapy-permissive state, with the potential to enhance the efficacy and durability of cancer immunotherapy.