Abstract
Background & aims: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer. Tumor-associated macrophages (TAMs) are integral to the tumor microenvironment (TME), where they facilitate the malignant progression of ICC and reshape the TME. TATA-binding protein-associated factor 15 (TAF15), a protein that binds both DNA and RNA, plays a pivotal role in inflammatory signaling pathways and is abnormally expressed in TAMs in ICC. However, the specific function of TAF15 in ICC-associated macrophages remains to be elucidated. This study aimed to investigate the regulatory effect of TAF15 in ICC-associated macrophages on ICC progression. Methods: The expression pattern of TAF15 in macrophages was assessed using multicolor fluorescence in ICC mouse tissues and patient samples (n = 5 per group). TAF15 expression in THP-1 cells was manipulated using CRISPR-Cas9 technology. The polarization index of TAMs, as well as the impact of TAMs on ICC proliferation, was evaluated through in vitro coculture. CUT&Tag and dual-luciferase reporter gene assay were used to identify potential regulatory elements of TAF15. M2pepLNP-siTAF15 was designed to target macrophages in a mouse ICC model for in vivo experiments, thereby confirming the role of TAF15 in TAMs on ICC progression (n = 5 per group). Results: TAF15 is highly expressed in TAMs (p <0.05) and promotes the polarization of macrophages towards the M2 phenotype, thereby furthering the progression of ICC (p <0.01). Mechanistically, TAF15 transcriptionally activates SOCS1 (p <0.001), inhibits the JAK2/STAT1 pathway, and suppresses macrophage polarization towards the M1 phenotype. M2pepLNP-siTAF15 can effectively target TAMs in the treatment of ICC. Conclusions: TAF15 has a pivotal role in ICC progression by affecting the phenotype of macrophages. Targeting TAF15 in TAMs emerges as a promising therapeutic strategy for the treatment of ICC. Impact and implications: Our study provides the first evidence that TATA-binding protein-associated factor 15 regulates tumor-associated macrophages polarization through the SOCS1/JAK2/STAT1 axis, unveiling a novel immunotherapeutic target for cholangiocarcinoma. The developed M2pep-LNP-siTAF15 nanodelivery system not only overcomes the challenge of targeted delivery, but its remarkable antitumor efficacy highlights strong potential for clinical translation. This work fundamentally advances our understanding of stromal-immune crosstalk in cholangiocarcinoma while offering a clinically actionable therapeutic strategy.