Immunocyte reprogramming empowers live-cell drug delivery: Mechanistic insights, delivery strategies, and clinical perspectives

Conventional drug-delivery systems (DDSs) for oncology often face challenges such as insufficient tumor selectivity, rapid systemic clearance, limited penetration across stromal and immune barriers, and suboptimal biocompatibility. Live immune cell-based drug-delivery systems (LCDDSs) overcome these limitations by exploiting the innate tumor-homing capacity, high biocompatibility, and dynamic tumor microenvironment (TME) interactions intrinsic to leukocytes, facilitating precise targeting with minimal systemic toxicity. Furthermore, immune cells act as "mobile microprocessors", actively converting precursor payloads into therapeutically functional cargos at the tumor site and dynamically reshaping the TME. Nonetheless, the clinical translation of LCDDSs remains impeded by limited drug-loading capacities, premature payload degradation, potential impairment of immune-cell function, and insufficient persistence in immunosuppressive environments. To overcome these hurdles, immune cell reprogramming <i>via</i> genetic, metabolic, or epigenetic modifications emerges as a promising strategy. Such interventions improve cellular fitness, enhance tumor infiltration, augment payload transport efficiency, confer programmable release profiles, mitigate cellular exhaustion, and increase adaptability to the hostile TME. This review systemically evaluates how immune cell reprogramming advances LCDDSs by examining mechanistic benefits, drug compatibility considerations, payload loading strategies, and design criteria essential for achieving clinical controllability, safety, and scalability. By integrating immune-cell engineering with cutting-edge drug delivery technologies, reprogrammed LCDDSs represent a versatile and powerful platform for next-generation precision oncology therapeutics.