Rearming mesenchymal stem cells with engineering strategies to combat cancer

Mesenchymal stromal/stem cells (MSCs) are garnering increasing attention as promising tumor-targeted delivery vehicles owing to their ability to sense inflammatory signals and access tumor-adjacent stromal niches. However, their plasticity in the tumor microenvironment also enables pro-tumor programs that promote angiogenesis, matrix remodeling, immune suppression, stemness, and therapy resistance. This review summarizes the molecular "homing hierarchy" that tumors exploit to recruit MSCs, primarily through the CXCL12/CXCR4 signaling axis, and integrates key pathways implicated in MSC-driven tumor progression. The focus is on "turning enemies into allies": engineering MSCs into programmable intratumoral factories and carriers to deliver defined anticancer payloads, including suicide gene systems, pro-apoptotic and anti-angiogenic effectors, immune-stimulatory cytokines, localized checkpoint blockade formats, and oncolytic viruses that combine intratumoral amplification with immunogenic remodeling. Furthermore, we summarize antigen-directed strategies aimed at enhancing delivery efficacy and strategies to precisely control the release of antitumor components to minimize off-target effects. Additionally, we discuss the formidable challenges associated with harnessing MSCs for antitumor therapy. Looking ahead, further optimization of MSC-based antitumor strategies through advanced genetic engineering and combination therapies holds the potential to significantly enhance their clinical efficacy.