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Determine transcriptomic changes in TGF-β–activated CAFs following Ce6@D4-EV–mediated photodynamic therapy (RNA-seq)

ABSTRACT: Solid tumors, including pancreatic ductal adenocarcinoma (PDAC), drive the activation of resident quiescent fibroblasts into cancer-associated fibroblasts (CAFs), fostering the development of dense desmoplastic stroma. This pathological remodeling restricts drug delivery and immune infiltration, exacerbating tumor progression. To disrupt this self-reinforcing cycle, we engineered a multifunctional therapeutic platform based on Midkine (MDK)-targeting nanobody (Nb)-functionalized extracellular vesicles (EVs) for precision photoimmunotherapy (PIT). The system leverages the overexpression of MDK in the tumor microenvironment (TME) to achieve selective targeting. In subcutaneous and orthotopic PDAC models, near-infrared (NIR) imaging confirmed the high tumor-targeting specificity of MDK-D4-EVs. Upon loading the clinically approved second-generation photosensitizer chlorine e6 (Ce6), Ce6@D4-EV mediated targeted photodynamic therapy (PDT) triggered immunogenic cell death (ICD), promoting dsDNA release from dying cancer cells and remodeling the immunosuppressive TME via cGAS-STING pathway activation in tumor-associated macrophages (TAMs). Concurrently, Ce6@D4-EV reprogrammed CAFs to suppress extracellular matrix (ECM) deposition, enhancing tumor vascular perfusion, alleviating hypoxia, and improving therapeutic agent penetration and immune cell infiltration. This dual modulation significantly augmented the efficacy of combined therapies, including immune checkpoint inhibitors (anti-PD-1 and anti-CD47 blockades), adoptive T cell therapy, and gemcitabine (Gem) chemotherapy, leading to marked survival benefits in preclinical models. Collectively, this engineered EV-based PIT platform offers a potent strategy to overcome stromal barriers in desmoplastic tumors and establishes a foundation for clinical translation of photoimmunotherapy strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE318328 | GEO | 2026/04/29

REPOSITORIES: GEO

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Project description:Introduction: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and has a survival rate of ~50% over five years. New treatment strategies are sorely needed to improve survival rates – and a better understanding of the mechanisms underlying tumorigenesis is needed to develop these strategies. The role of the tumor microenvironment (TME) has increasingly been identified as crucial in tumor progression and metastasis. One of the main constituents of the TME, cancer-associated fibroblasts (CAFs), plays a key role in influencing the biological behavior of tumors. Multiple mechanisms contribute to CAF activation, such as TGFβ signaling, but the role of extracellular vesicles (EVs) in CAF activation in OSCC is poorly understood. Assessing the impact of oral cancer-derived EVs on CAF activation will help to better illuminate OSCC pathophysiology and may drive development of novel treatments options. Materials and Methods: EVs were isolated from OSCC cell lines (Cal 27, SCC-9, SCC-25) using differential centrifugation. Nanoparticle tracking analysis was used for EV quantification and size characterization, and Western blot to confirm the presence of EV protein markers. Oral fibroblasts were co-cultured with enriched EVs, TGFβ, or PBS over 72 hours to assess activation. Flow cytometry was used to evaluate the difference in CAF markers. RNA collected from fibroblasts was extracted and the transcriptome was sequenced. Conditioned media from the co-cultures was evaluated with cytokine array profiling. Results: OSCC-derived EVs can activate oral fibroblasts into CAFs that are different from those activated by TGFβ, suggesting different mechanisms of activation and different functional properties. Gene set enrichment analysis using expression data from activated CAFs showed several upregulated inflammatory pathways in those CAFs exposed to OSCC-derived EVs. Marker genes for inflammatory CAF subtypes were also upregulated. This was not seen in CAFs activated by TGFβ. Finally, cytokine array analysis on secreted proteins from CAFs revealed elevated levels of several pro-inflammatory cytokines from CAFs activated by EVs, for instance IL-8 and CXCL5. Conclusions: Taken together, our results reveal the ability of OSCC-derived EVs to activate fibroblasts into CAFs. These CAFs seem to have unique properties, differing from TGFβ-activated CAFs. Gaining an understanding of the interplay between EVs and stromal cells such as CAFs could lead to further insights into OSCC tumorigenesis and potential novel therapeutics.

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Determine transcriptomic changes in TGF-β–activated CAFs following Ce6@D4-EV–mediated photodynamic therapy (RNA-seq)

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