CHST1 Drives Immunotherapy Resistance in Triple‐Negative Breast Cancer by Orchestrating an Immunosuppressive Microenvironment via the NKRF–CCL20–Macrophage Axis

Vollständiger Abstract

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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.