Manganese-Polydopamine Nano-Immunomodulator Synergistically Activates the STING Pathway and Pyroptosis for Renal Cell Carcinoma Immunotherapy 2308359

Abstract Introduction Renal cell carcinoma (RCC) remains highly resistant to conventional therapies, highlighting the need for innovative treatments. Tumor-associated macrophages (TAMs) play a critical role in RCC progression by promoting immune evasion and supporting tumor growth. Manganese ions have been shown to activate the cGAS-STING pathway, enhancing anti-tumor immunity. However, precise targeting and controlled release of manganese in the tumor microenvironment remain major challenges. Methods We developed manganese-polydopamine nano-immunomodulators (PDA-Mn-HA NPs), coated with hyaluronic acid (HA), to selectively target CD44 receptors on TAMs and RCC cells. These nanoparticles were characterized for their size, surface charge, and manganese release profile. In vitro, we assessed their ability to induce M1 macrophage polarization, stimulate cytokine production, and generate reactive oxygen species (ROS). We also evaluated their potential to induce pyroptosis in RCC cells and tested their therapeutic effects in a preclinical RCC mouse model. Results PDA-Mn-HA NPs effectively induced M1 macrophage polarization, promoting the release of pro-inflammatory cytokines and chemokines crucial for immune activation. Transcriptomic analysis showed significant changes in gene expression related to immune response in macrophages, confirming the nanoparticles’ immunomodulatory role. In RCC cells, PDA-Mn-HA NPs induced ROS-mediated pyroptosis through the caspase-3/GSDME pathway, further enhancing immune system activation. In vivo, PDA-Mn-HA NPs not only inhibited RCC tumor growth but also increased immune cell infiltration, particularly cytotoxic T cells, reshaping the tumor microenvironment to promote anti-tumor immunity. Conclusion PDA-Mn-HA NPs offer a promising strategy for RCC treatment by synergistically targeting both TAMs and RCC cells. This dual action enhances anti-tumor immunity and addresses the challenges of manganese ion delivery, presenting a novel approach to RCC immunotherapy. Funding Source This work was funded by the National Natural Science Foundation of China (Grant No. 81801913) and the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2020B1515020036). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)