基于聚合物的纳米药物通过表观遗传重编程免疫抑制性肿瘤微环境增强声动力治疗

While sonodynamic therapy (SDT) has shown promise in treating triple-negative breast cancer (TNBC) due to its non-invasive nature, deep tissue penetration, and induction of immunogenic cell death (ICD), its efficacy remains limited by the complex immunosuppressive tumor microenvironment (TME). In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric).

GdNPs/Ce6-Ric effectively accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and release Ce6 and Ric in response to the acidic TME. Upon ultrasound stimulation, GdNPs/Ce6-Ric induce cancer cell apoptosis and trigger ICD by generating reactive oxygen species (ROS), which activate cytotoxic T cells and promote tumor cell elimination.

Notably, the epigenetic modulation by Ric within the immunosuppressive TME increased the proportion of natural killer (NK) cells and cytotoxic T cells while decreasing the population of immunosuppressive regulatory T (Treg) cells. This modulation synergistically enhanced the anti-tumor effects of SDT by downregulating the HDAC6/p-STAT3/PD-L1 pathway.

Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation.

Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC.