Abstract Background: Aging profoundly remodels the pancreatic tumor microenvironment (TME), where senescent cancer-associated fibroblasts (senCAFs) accumulate and promote tumor progression. However, the metabolic cues derived from aged tumor cells that induce fibroblast senescence and mediate immune suppression remain poorly understood. Methods: Integrated analyses of murine and human single-cell RNA-sequencing datasets combined with multiplex immunofluorescence (mIF) revealed a marked enrichment of p16+ senCAFs in aged pancreatic ductal adenocarcinoma (PDAC). Targeted metabolomics and isotope tracing identified lactate as a key metabolite driving fibroblast senescence. Lactyl-proteomics, ATAC-seq, CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2075.
Tu et al. (Fri,) studied this question.
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