MSC-delivered CXCL10 for solid tumors: Navigating the translational hurdles from precept to clinic

The recent study by Yoon et al. (Biomed Pharmacother. 2025) presents an innovative strategy to augment adoptive T cell therapy (ACT) for solid tumors by employing mesenchymal stromal cells (MSCs) engineered for tumor-targeted delivery of CXCL10. While the preclinical data compellingly demonstrate enhanced T-cell infiltration and antitumor efficacy, a substantive critique reveals profound challenges that threaten its clinical translation. The foundational premise of using MSCs as a delivery vehicle is critically undermined by their well-documented functional plasticity; within the tumor microenvironment (TME), these cells risk adopting pro-tumorigenic phenotypes, including differentiation into cancer-associated fibroblasts that promote desmoplasia or secretion of factors like VEGF that drive angiogenesis. Concurrently, the pleiotropic nature of CXCL10 signaling represents a significant biological paradox. While intended to recruit cytotoxic T-cells, this chemokine axis is also a potent recruiter of CXCR3 + immunosuppressive populations, notably regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby potentially fostering an immune-suppressive niche that could counteract therapeutically recruited effectors. Furthermore, the translational pathway is fraught with additional hurdles: the limited fidelity of immunocompetent murine models to human TME heterogeneity, significant scalability and batch-to-batch variability issues in manufacturing clinical-grade engineered MSCs, and unresolved safety concerns pertaining to lentiviral-mediated transgenesis. Therefore, while conceptually elegant, the clinical viability of this platform is contingent upon future studies providing rigorous in vivo fate-mapping of administered MSCs, comprehensive immune profiling to delineate the net immunomodulatory outcome, and the development of robust combinatorial strategies, such as coupling with immune checkpoint blockade, to mitigate these inherent risks. Addressing these core issues is paramount to advancing this potent preclinical proof-of-concept into a safe and effective therapeutic modality.