The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy. Although many cancers originate in mucosal tissues, current RNA cancer vaccines are mainly administered non-mucosally. Here, we developed a non-invasive intranasal cancer vaccine utilizing circular RNA encapsulated in lipid nanoparticles to induce localized mucosal immune responses. This strategy elicited potent anti-tumor T cell responses in preclinical lung cancer models while mitigating the systemic adverse effects commonly associated with intravenous RNA vaccination. Specifically, type 1 conventional dendritic cells were indispensable for T cell priming post-vaccination, with both alveolar macrophages and type 1 conventional dendritic cells boosting antigen-specific T cell responses in lung tissues. Moreover, the vaccination facilitated the expansion of both endogenous and adoptive transferred antigen-specific T cells, resulting in robust anti-tumor efficacy. Single-cell RNA sequencing revealed that the vaccination reprograms endogenous T cells, enhancing their cytotoxicity and inducing a memory-like phenotype. Additionally, the intranasal vaccine can modulate the response of CAR-T cells to augment therapeutic efficacy against tumor cells expressing specific tumor-associated antigens. Collectively, the intranasal RNA vaccine strategy represents a novel and promising approach for developing RNA vaccines targeting mucosal malignancies.
© 2025. The Author(s).

The inflammatory microenvironment influences dendritic cell-mediated antigen presentation to regulate asthma Th2 inflammation. The scavenger receptor is expressed on DCs and regulates antigen presentation and T priming. However, whether the transmembrane scavenger receptor (SR-PSOX/CXCL16) regulates the phenotype and antigen presentation function of DCs remains unclear. We found that CXCL16 is mainly expressed on DCs in the lung tissues of asthma patients and asthma mice. CXCL16 knockout led to the suppression of airway inflammation, mucus overproduction, and airway hyperresponsiveness in Aspergillus-induced asthma. In addition, the adoptive transfer of Aspergillus-pulsed DCs shows the CXCL16+ DCs exerted a promoting role in airway inflammation, the CXCL16- DCs inhibit airway inflammation. Additionally, RNA sequencing and flow cytometry data revealed that CXCL16 knockout inhibits airway inflammation by suppressing the antigen processing and presentation function of DCs, which was mediated by MHC II chaperone H2-DM. Furthermore, we found CXCL16 knockout suppressed dendritic cells differentiated forward to cDC2b subtype which is mainly charged with antigen presentation to T cell. In conclusion, we found that CXCL16 downregulated the capacity of DC antigen processing and presentation to suppress airway inflammation by reducing H2-DM expression which mediated DC differentiation. The study suggested that inhibition of CXCL16 can be a potential therapy for asthma.
© 2025. The Author(s).

Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) resolve acute inflammation and repair the injured lung after viral pneumonia. Vimentin is a critical protein in the distal pole complex (DPC) of Tregs. This study reveals the inhibitory effect of vimentin on the suppressive and reparative capacity of Tregs. Treg-specific deletion of vimentin increases Helios+interleukin-18 receptor (IL-18R)+ Tregs, suppresses inflammatory immune cells, and enhances tissue repair, protecting Vimfl/flFoxp3YFP-cre mice from influenza-induced lung injury and mortality. Mechanistically, vimentin suppresses the induction of amphiregulin, an epidermal growth factor receptor (EGFR) ligand necessary for tissue repair, by sequestering IL-18R to the DPC and restricting receptor-ligand interactions. We propose that vimentin in the DPC of Tregs functions as a molecular switch, which could be targeted to regulate the immune response and enhance tissue repair in patients with severe viral pneumonia.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.
© 2024. The Author(s).

Multiple sclerosis (MS) is characterized by neuroinflammation, oxidative stress, iron toxicity and mitochondrial dysfunction. Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely held to drive tissue damage, yet the specific roles of central nervous system (CNS)- resident versus CNS-invading MPs remain unclear. Here, by combining single-cell profiling with conditional gene targeting, we systematically dissected and interfered with ROS production across CNS MPs in a preclinical model for neuroinflammation. We show that CNS-invading monocyte derived cells (MdCs) exhibit a higher oxidative stress gene signature and produce more ROS compared to CNS-resident microglia. While NADPH oxidase 2 (NOX2), a phagocytic source of ROS, proved redundant, our findings underscore the critical role of mitochondrial ROS (mtROS) in driving oxidative tissue damage. Quenching mtROS through mitocatalase overexpression in MdCs, but not microglia, significantly alleviated neuroinflammation in mice. Thus, our study resolves a longstanding controversy, identifying MdCs as the primary driver of ROS-mediated neuropathology.