CHST1 Drives Immunotherapy Resistance in Triple-Negative Breast Cancer by Orchestrating an Immunosuppressive...

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.