Abstract In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumo
Abstract In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumor” toxicities, highlighting the need for small-molecule approaches with reduced immunogenicity. This study investigates the synergistic potential of norcantharidin (NCTD) and lomitapide (lomi) in selectively restoring CCL4 expression by deactivating the tumor intrinsic β-catenin pathway. Due to its similar lipophilicity to lomi and potential to suppress β-catenin, NCTD prodrug (C12) was selected to be co-encapsulated with lomi in a nanoparticle-mediated co-delivery system (NP“C12 + lomi”). The NP“C12 + lomi” formulation exhibited a high encapsulation rate, uniform particle size, and suitability for therapeutic use. It effectively inhibited the proliferation of 4T1 cells and restored CCL4 expression. In both primary breast tumor and surgically resected tumor mouse models, NP“C12 + lomi” significantly increased the proportion of CD8+ cells in primary tumors, blood, and lung metastases, approximately doubling their presence. This led to a prolongation of median survival in mice to 59 days. Furthermore, when combined with an immune checkpoint inhibitor, NP“C12 + lomi” substantially inhibited tumor growth and lung metastasis without affecting body weight or causing major tissue or organ damage. This was attributed to the controlled dissociation of the nanoparticle and the subsequent modulation of C12 and lomi, which mitigated CCL4-related toxicity. This study provides valuable insights into the safe production of chemokines using a small-molecule pair through a nanosystem and presents a robust chemo-immunological cascade therapy strategy, demonstrating significant efficacy against malignant metastatic tumors. Graphical abstract
