Steroid Receptor Coactivator‐1 Drives Tumor‐Associated Macrophage Reprogramming by Mediating MMP12 Transcription in Pancreatic Cancer Perineural Invasion

作者：Ke Cheng, Liang Liu, Miaomiao Gong, Yuke Ji, Chunmei Bai, Xiangqian Guo, Hui Chen, Jinjin Pan, Ying Zhang, Yuhui Yuan · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202416575 · 被引用次数：4 · 研究领域：Immune cells in cancer、Cancer, Stress, Anesthesia, and Immune Response、Histone Deacetylase Inhibitors Research

Perineural invasion (PNI) is a hallmark of pancreatic cancer aggressiveness. However, the feasibility of manipulating tumor-associated macrophage (TAM) reprogramming to influence PNI development remains unclear. Methods: Using in vitro (tumor-DRG co-culture) and in vivo (sciatic nerve injection) models coupled with protein identification by liquid chromatography-mass spectrometry (LC-MS) and ChIP-seq, the role of steroid receptor coactivator-1 (SRC-1) is investigated in TAM reprogramming and PNI. SRC-1 is up-regulated in TAMs and promotes PNI by binding to signal transducer and activator of transcription 1(STAT1) to enhance matrix metallopeptidase 12 (MMP12) transcription. SRC-1 knockdown attenuated M2-like characteristics in TAMs, reduced MMP12 secretion, and suppressed PNI. Importantly, blocking the SRC-1/STAT1/MMP12 axis (using SRC-1-KO TAMs or MMP12 inhibitors) attenuated PNI progression in vivo. SRC-1 reprograms TAMs via STAT1-mediated MMP12 activation to facilitate PNI. Targeting SRC-1 disrupts this axis and presents a novel therapeutic strategy against PNI in pancreatic cancer.