Targeting Hypoxia and Autophagy Inhibition via Delivering Sonodynamic Nanoparticles With HIF‐2α Inhibitor for Enhancing Immunotherapy in Renal Cell Carcinoma

Immune checkpoint blockers (ICBs) therapy stands as the first‐line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia‐responsive polymer (Poly(4,4′‐azobisbenzenemethanol‐PMDA)‐mPEG5k, P‐APm) encapsulating both a HIF‐2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from “immune‐cold” to “immune‐hot”, thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC. This study reports on a hypoxia‐responsive nanoparticle loaded with a HIF‐2α inhibitor (belzutifan), and the ultrasonic sensitizer (Chlorin e6, Ce6), which can inhibit tumor hypoxia and autophagy signaling pathways, and downregulate PD‐L1 expression in tumor cells, leading to improved efficacy of αPD‐1. Overall, it presents a promising strategy of targeted therapy combined with immunotherapy for treating renal cell carcinoma.