Abstract
BACKGROUND: Immune checkpoint inhibitor (ICI) therapies have marked a significant breakthrough in tumor immunotherapy. However, their clinical efficacy remains suboptimal in many cases. Emerging evidence indicates that resistance to ICIs is largely driven by the immunosuppressive nature of the tumor microenvironment (TME). Modulating the TME-through conventional chemotherapy or anti-angiogenic therapies has been shown to enhance immune activation and improve the therapeutic response to ICIs. METHODS: In this study, we developed epirubicin (EPI)-loaded lipid nanoparticles, termed DPPA(EPI) LNPs, which integrate the chemotherapeutic agent EPI with the anti-angiogenic lipid DPPA, enabling co-delivery and targeted enrichment within tumors. The cytotoxicity and anti-vascular endothelial cell tube formation properties of DPPA(EPI) LNPs were tested in vitro. The biosafety, anti-tumor ability and immunoactivities were tested on orthotopic tumor models of both breast cancer and hepatoma in vivo. RESULTS: DPPA(EPI) LNPs showed the advantages of uniformed particle size, high stability, good sustained-release effect. Compared to free drug, DPPA(EPI) LNPs significantly prolonged blood circulation (21.7% remaining at 12 h vs.16.5% at 30 min for free drug), enhanced tumor accumulation (18.4-fold change than free drug) and had well biological safety. In vivo, DPPA (EPI) LNPs showed excellent anti-tumor therapeutic efficacy by significantly inhibiting tumor cell proliferation (Ki67† cells reduced by 55%), reducing tumor angiogenesis (vascular density by 60%), and inducing stronger immunogenic cell death effect both in 4T1 orthotopic tumor model and Hepa1-6 orthotopic tumor model. And the treatment of DPPA (EPI) LNPs combined with programmed cell death protein 1 (PD-1) inhibitor further improved the activation of anti-tumor immunity in the TME, which leads to more significant inhibition of the tumor growth. CONCLUSION: This dual-function nanoplatform-combining chemotherapy and anti-angiogenic therapy-substantially improved the efficacy of PD-1 blockade in both breast cancer and hepatocellular carcinoma (HCC) models. These findings offer a promising strategy and experimental foundation for TME modulation and the advancement of combination immunotherapy.