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.
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.
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.
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.
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).
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
CAR T cell therapy has shown success in treating hematologic malignancies but faces challenges in solid tumors due to antigen heterogeneity and the complex tumor microenvironment (TME). CAFs expressing fibroblast activation protein (FAP) contribute to immune suppression by creating physical barriers and immune-suppressive environment that blocks T cell infiltration and persistence. Overcoming these barriers is crucial for enhancing CAR T cell therapy in solid tumors.
We engineered a modular CAR T cell platform using anti-FLAG CAR T cells conjugated with FLAG-tagged monoclonal antibodies, allowing flexible targeting of both tumor cells and CAFs. This platform was tested in B-cell lymphoma and pancreatic cancer models, both in vitro and in vivo. Cytotoxicity was evaluated through flow cytometry. TME remodeling and cytokine production were assessed using immunostaining, multiplex cytokine assays, and qPCR. In vivo efficacy was evaluated in subcutaneous and orthotopic models.
In B-cell lymphoma, FLAG CAR T cells, combined with FLAG-tagged CD19 antibodies, exhibited strong anti-tumor activity, significantly increasing tumor cell lysis and achieving cytotoxicity comparable to traditional CD19 CAR T cell therapies. In solid tumor models, FLAG CAR T cells, in combination with FLAG-tagged antibodies targeting FAP+ CAFs and Claudin18.2+ tumor cells, enhanced immune cell infiltration and significantly suppressed tumor growth. This dual-targeting strategy disrupted the TME-induced immune suppression, reduced collagen deposition, and boosted T cell activity, resulting in notable tumor growth inhibition and prolonged survival in both subcutaneous and orthotopic pancreatic cancer models.
This CAR T cell platform enables dual targeting of tumor cells and CAFs, overcoming immune suppression in solid tumors. This approach enhances immune activation, reshapes the TME, and provides a promising strategy for improving CAR T cell therapy in solid tumors.
This study was funded by the National Natural Foundation of China (No. 81970632), Guangdong Science and Technology Department (Nos. 2020B1212060018 and 2020B1212030004), Guangdong Basic and Applied Basic Research Foundation 2025A1515011234.
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
