miR-203a Reactivation as a Dual Tumor-Suppressive and Innate Immune–Reprogramming Strategy in Non–Small Cell Lung Cancer

Non–small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite the introduction of platinum-based chemotherapy and immune checkpoint inhibitors, a substantial proportion of patients fail to respond or develop resistance, underscoring the urgent need for innovative therapeutic strategies capable of targeting both tumor-intrinsic oncogenic pathways and immune escape mechanisms. MicroRNA-203a (miR-203a) is significantly downregulated in NSCLC and has been associated with poor prognosis. Restoration of miR-203a suppresses tumor cell proliferation and survival, supporting its tumor-suppressive function. Beyond its canonical post-transcriptional role, our preliminary data and prior work indicate that extracellular GU-rich miRNAs, including miR-203a, can activate innate immune pathways through TLR7/8 signaling, promoting functional reprogramming of plasmacytoid dendritic cells and enhancing NK-cell–mediated cytotoxicity. We hypothesize that therapeutic reactivation of miR-203a exerts a dual anti-tumor effect in NSCLC: (i) suppression of tumor-intrinsic oncogenic signaling networks and (ii) restoration of innate immune competence within the tumor microenvironment. This project aims to mechanistically dissect these complementary activities, define the molecular targets of miR-203a in tumor cells, and characterize its capacity to reprogram innate immune responses. Using state-of-the-art technologies—including multi-line in vitro systems, organotypic models, single-cell transcriptomics, and advanced in vivo approaches—we will establish the therapeutic potential and translational relevance of miR-203a reactivation. By integrating tumor biology and innate immune modulation within a unified therapeutic framework, this study seeks to provide proof-of-concept for a dual-compartment strategy to overcome immune dysfunction and improve treatment responsiveness in NSCLC.