Engineered mesenchymal stem/stromal cells against cancer

Abstract

Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.

Fig. 1. Engineered MSCs function as delivery vehicles in cancer therapy.

MSCs are engineered to leverage their tumor-homing capabilities while exhibiting low immunogenicity, facilitating the targeted delivery of therapeutic proteins, microRNAs (miRNAs), prodrugs, and oncolytic viruses directly into the tumor microenvironment and activating antitumor immunity, which aims to enhance therapeutic efficacy while minimizing off-target effects. Key advantages of this approach include precise tumor targeting, improved intratumoral penetration, sustained tumoricidal effects, and higher therapeutic safety.

Fig. 2. The multifaceted impacts of engineered MSCs on tumor progression.

MSCs from different sources, including adipose tissue, umbilical cord, bone marrow, dental pulp, and lung, are engineered through viral infection and genetic modification to express therapeutic factors, such as interferons and interleukins, miRNAs, prodrugs, and oncolytic viruses. These engineered MSCs contribute to cancer therapy by modulating tumor biology—enhancing tumor apoptosis, inhibiting angiogenesis, reducing tumor cell migration, and modulating inflammatory infiltration.

Fig. 3. The translational pathway of engineered MSCs from laboratory research to clinical application.

Initially, the preparation and modification of MSCs involve meticulous donor selection, considering factors such as health status, genetic background, sex, age, and tissue origin. Subsequently, bioengineering approaches—such as particle engineering, genetic modifications, and oncolytic virus incorporation—are integrated into standardized manufacturing processes to produce engineered MSCs. In the intermediate stage, rigorous quality control measures and potency assessments are conducted. These steps include monitoring cell viability, ensuring genetic stability, and evaluating the release of biologic factors, along with conducting in vitro and in vivo efficacy tests. Characterization of the immune microenvironment and tumorigenic phenotypes further elucidates the therapeutic potential and underlying mechanisms of action. Finally, during clinical trials and application, patient stratification is performed based on factors such as pathological grading, disease stage and severity, prior treatments, drug susceptibility, and oncogenomic profiles. This stratification enables the formulation of personalized therapeutic regimens, incorporating synergistic treatment strategies, tailored administration routes, continuous tumor monitoring, nutritional support, and clinical follow-up. Together, these steps enable the safe, effective, and precise translation of engineered MSC therapies from bench to bedside.