Long non-coding RNAs (lncRNAs) exert essential regulatory effects on the activation and phenotypic conversion of cancer-associated fibroblasts (CAFs). Nevertheless, their involvement has yet to be thoroughly explored using single-cell approaches. Leveraging comprehensive integrated single-cell transcriptomic datasets, we identified lncRNAs with abnormal expression patterns specifically within CAFs, the primary cellular element of the tumor microenvironment. Our analysis uncovered a pan-cancer pattern of pronounced CAF-restricted reduction in Maternally Expressed Gene 3 (MEG3) levels, together with a rise in the fraction of MEG3-positive cells. This alteration appears linked to m6A-dependent post-transcriptional control mechanisms. Pseudotime trajectory reconstruction across key CAF subpopulations revealed that higher MEG3 expression upregulates PDGFRA, which in turn facilitates CAF activation and their shift toward a MEG3-positive adipogenic CAF (MACAF) state. This MACAF subpopulation displays enhanced vulnerability to Dasatinib. Intercellular communication networks associated with MACAFs indicated that these cells stimulate epithelial-mesenchymal transition in cancer cells through TGF-β signaling, thereby increasing tumor cell motility and supporting tumor advancement and invasive behavior. Furthermore, individuals exhibiting higher MACAF scores demonstrated significantly worse survival outcomes and diminished efficacy of immune checkpoint blockade therapy, pointing to a role for MACAFs in establishing an immunosuppressive milieu. Collectively, this work elucidates the contribution of MEG3 to CAF activation and emphasizes the clinical relevance of the MACAF score as a potential biomarker for optimizing treatment regimens that incorporate Dasatinib alongside immunotherapy.
