Comprehensive characterization of tumor therapeutic response via simultaneous mapping of cell size, density, and transcytolemmal water exchange.

The evaluation of tumor response to neoadjuvant chemotherapy is critical for the personalized management of cancer patients, aiming to minimize unnecessary toxicity, costs, and treatment delays. Current imaging techniques primarily depend on detecting tumor volume changes, which reflect downstream effects. In contrast, advanced microstructural diffusion MRI (dMRI) methods offer cellular-level insights but are limited by biased estimates of cell density due to oversimplified biophysical models. We present a novel dMRI-based approach, EXCHANGE, which incorporates transcytolemmal water exchange into a quantitative multi-compartmental biophysical model. This method enables simultaneous mapping of cell size, density, and transcytolemmal water exchange, providing a comprehensive characterization of tumor microstructure. Validation through computer simulations and in vitro studies demonstrated the good accuracy of EXCHANGE-derived metrics. In a proof-of-concept study, EXCHANGE was applied to animal models and patients with triple-negative breast cancer, showcasing its potential to evaluate tumor therapeutic response to neoadjuvant chemotherapy. EXCHANGE offers a unique capability to characterize tumor microstructural properties at the cellular level, paving the way for improved monitoring of treatment response in clinical settings.