Macrophage-delivered Nifuroxazide Reprograms Immunosuppressive Microenvironment and Synergizes with Oxaliplatin for Enhanced Anti-Hepatocellular Carcinoma Therapy

Nifuroxazide (NFX), an antibacterial agent, also exhibits notable antitumor effects by inhibiting STAT3 signaling, which is often aberrantly activated and linked to chemoresistance in tumors such as hepatocellular carcinoma (HCC). Combining NFX with chemotherapy may enhance therapeutic efficacy, but its poor solubility limits oral bioavailability. To address this, we developed a biomimetic delivery system by loading NFX into murine macrophage-like RAW264.7 cells (Mφ-NFX). This strategy aims to improve drug delivery, enhance antitumor effects, with the potential to circumvent or overcome drug resistance. We evaluated the efficacy of Mφ-NFX alone and in combination with Oxaliplatin in vitro and in preclinical HCC models. Macrophages effectively carried and delivered NFX to tumor cells and tissues without significant toxicity to the carriers. Additionally, NFX promoted macrophage polarization toward the M1 phenotype within the tumor microenvironment. Mφ-NFX significantly inhibited tumor growth and increased the M1/M2 macrophage ratio. Co-treatment with Mφ-NFX and Oxaliplatin demonstrated enhanced tumor suppression and modulation of the tumor microenvironment. Mechanistically, NFX and Oxaliplatin acted synergistically via inhibition of the AKT/β-catenin pathway. In conclusion, this macrophage-based NFX delivery platform offers improved antitumor activity and sensitization to chemotherapy, presenting a promising strategy for HCC treatment.