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

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.