Biomed Pharmacother. 2025 Sep 20;192:118579. doi: 10.1016/j.biopha.2025.118579. Online ahead of print.
ABSTRACT
Limited T cell infiltration into solid tumors remains one of the major obstacles to successful cancer immunotherapy, particularly for adoptive cell therapy (ACT). Although the chemokine CXCL10 recruits T cells, its direct therapeutic application is hampered by poor pharmacokinetics, systemic leakage, and failure to establish stable concentration gradients required for effective cell migration. To overcome these challenges, we engineered mesenchymal stromal cells (MSCs) to co-express NAD(P)H quinone oxidoreductase 1 (NQO1) for enhanced survival and CXCL10-Fc fusion protein for sustained chemokine delivery (NIP-MSCs). The engineered MSCs exhibited resilience to tumor microenvironment conditions through improved redox homeostasis, resulting in enhanced persistence and sustained IP10-Fc production in vivo. Crucially, tumor-targeted delivery of CXCL10-Fc established potent chemotactic gradients with minimal systemic leakage, dramatically increasing both endogenous and adoptively transferred T cell recruitment to tumor site. In syngeneic mouse models, NIP-MSC treatment significantly suppressed tumor growth through enhanced CD8+ T cell infiltration. When combined with ACT in melanoma models, NIP-MSCs resulted in superior tumor control and significantly prolonged survival compared to conventional approaches. This work validates NIP-MSCs as a promising platform to overcome T cell exclusion and potentiate immunotherapy efficacy in solid tumors.
PMID:40975901 | DOI:10.1016/j.biopha.2025.118579
