ACS Appl Mater Interfaces. 2025 Dec 1. doi: 10.1021/acsami.5c15987. Online ahead of print.

ABSTRACT

Gene therapy represents a promising strategy for treating lung cancer, with the potential to inhibit the proliferation of cancerous cells and induce apoptosis. However, current gene therapy for lung cancer encounters challenges with delivery, targeting, and safety, such as off-target effects, immune responses, and the necessity for better delivery methods. Here, we introduce gene therapy using the key regulator in lung adenocarcinoma, runt-related transcription factor 3 (RUNX3), within exosomes (Exos), which are known for their biocompatibility and ability to selectively target cancer cells. We packaged the RUNX3 plasmid DNA into human exosomes (hExo-Rs), designed to target and induce apoptosis in cancer cells, resulting in a viability decrease to 43.3%. Normal fibroblasts remained viable at 96.0%, confirming the safety of hExo-Rs for future therapies. We delivered hExo-Rs to cancer spheroids, examined their effects, and found that cytokines from treated cells promote M1 macrophage polarization, emphasizing their potential for immunotherapy. We developed a hydrogel platform for the targeted 14-day release of RUNX3 pDNA by attaching hExo-Rs to gelatin using microbial transglutaminase, which enables the selective decrease in cancer cell viability and confirms apoptosis. Our demonstration of RUNX3 gene therapy with Exos presents selective anticancer effectiveness and the promise of clinical use through localized, sustained release using the hydrogel.

PMID:41325015 | DOI:10.1021/acsami.5c15987

Cell Stem Cell. 2025 Jun 6:S1934-5909(25)00191-2. doi: 10.1016/j.stem.2025.05.011. Online ahead of print.

ABSTRACT

Deciphering interactions between tumor micro- and systemic immune macroenvironments is essential for developing more effective cancer diagnosis and therapeutic strategies. Here, we established a gel-liquid interface (GLI) co-culture model of lung cancer organoids (LCOs) and paired peripheral-blood mononuclear cells (PBMCs), featuring enhanced interactions between immune cells and tumor organoids for optimized simulation of in vivo systemic anti-tumor immunity. By constructing a cohort of lung cancer patients, we demonstrated that the responses of GLI models under αPD1 treatment reflected the immunotherapy outcomes of the corresponding patients precisely. Furthermore, we dissected the various tumor immune processes mediated by PBMC-derived T cells within GLI models through functional multi-omics analyses, along with the characterization of circulating tumor-reactive T cells (GNLY⁺CD44⁺CD9⁺) with effector memory-like phenotypes as a potential indicator of immunotherapy efficacy. Our findings indicate that the GLI co-culture model can be used to develop diagnostic strategies for precision immunotherapies, as well as understanding the underlying mechanisms.

PMID:40513558 | DOI:10.1016/j.stem.2025.05.011