CHST1通过NKRF-CCL20-巨噬细胞轴调控免疫抑制微环境，驱动三阴性乳腺癌对免疫疗法产生耐药性

Abstract

Triple‐negative breast cancer (TNBC) derives limited benefit from immune checkpoint blockade, largely owing to primary resistance shaped by the tumor immune microenvironment. Here, baseline transcriptomic profiling of a neoadjuvant chemoimmunotherapy cohort identified carbohydrate sulfotransferase 1 (CHST1) as a candidate resistance‐associated gene. High CHST1 expression was associated with poor immunotherapy response and inferior clinical outcome across clinical datasets. Functionally, CHST1/Chst1 had minimal effects on tumor‐cell‐intrinsic proliferation, migration, or invasion in vitro, but promoted tumor growth in an immune context–dependent manner in vivo. Mechanistic analyses support a model in which CHST1 associates with NF‐κB‐repressing factor (NKRF) and limits its nuclear accumulation, a localization change associated with increased NF‐κB‐related CCL20 expression. Tumor‐cell CCL20 perturbation and rescue experiments further supported a functional contribution of CCL20 to macrophage recruitment and M2‐like remodeling. Pharmacologic CCR6 blockade enhanced the antitumor activity of anti–PD‐1 therapy in syngeneic TNBC models. Finally, a CHST1–NKRF–CCL20 expression signature showed potential value for stratifying immunotherapy response. Collectively, this study supports a CHST1–NKRF–CCL20 regulatory model and identifies CCR6 blockade as a potential therapeutic strategy. Proposed model of CHST1‐associated immune remodeling in triple‐negative breast cancer. In CHST1‐low tumors, greater nuclear accumulation of NKRF is associated with repression of an NF‐κB‐related CCL20 transcriptional program and an immune‐inflamed microenvironment. In CHST1‐high tumors, CHST1 associates with NKRF and limits its nuclear accumulation, contributing to increased CCL20 expression, M2‐like macrophage enrichment, reduced cytotoxic T‐cell infiltration, and an immune‐suppressive tumor microenvironment.