Exosome-mediated delivery of miRNA-1290 inhibitor enhances JNK-dependent tissue-resident memory T cell immunity in prostate cancer

Abstract Prostate cancer (PCa) is a leading malignancy in men, particularly challenging in its advanced stages due to treatment resistance and immune evasion. MicroRNA-1290 (miR-1290) was identified to be implicated in tumor progression, but its role in PCa remains insufficiently characterized. Recent advances in exosome-based delivery systems provide opportunities to target oncogenic miRNAs in vivo. This study aimed to evaluate the therapeutic efficacy and immunomodulatory mechanism of exosome-delivered miR-1290 inhibitor in a PCa mouse model. Exosomes derived from RM-1 cells were loaded with miR-1290 inhibitor and intratumorally administered into TRAMP mice. Tumor volume, body weight, and overall survival were monitored. Safety profiles were evaluated through liver and kidney function tests. Single-cell RNA sequencing (scRNA-seq) and flow cytometry were used to profile intratumoral immune cells, particularly CD8⁺ tissue-resident memory T cells (Trm). Cytokine levels and MAPK signaling activity were assessed, JNK, ERK, and p38 signaling pathways were selectively inhibited to identify immune mechanisms. MiR-1290 expression was elevated in prostate tumor tissues and was significantly suppressed by exosome-delivered miR-1290 inhibitor. Treated mice exhibited reduced tumor growth, improved body weight, and prolonged survival compared with controls, without evident systemic toxicity. scRNA-seq revealed a marked increase of CD8⁺ Trm cells in the prostate tumor tissues of treated mice, with enrichment of inflammatory and immune response pathways, particularly MAPK signaling. The results of the flow cytometry experiment also indicated a marked increase of T cells, CD8 T cells, and CD8 Trm cells in the tumor tissues of miR-1290 inhibitor treated mice. Inhibiting JNK, but not ERK or p38, suppressed IFN-γ and TNF-α production by Trm. Exosome-mediated delivery of a miRNA-1290 inhibitor effectively remodels the prostate tumor microenvironment by enhancing JNK-dependent Trm activation, resulting in efficient and durable antitumor immunity. These findings support miRNA-1290 as a promising therapeutic target and highlight exosome-based RNA therapeutics as a novel strategy for prostate cancer management, warranting further translational development.