Tumor-specific MHC-II guides anthracycline exemption and immunotherapy benefit in breast cancer.

BACKGROUND: Anthracycline-based chemotherapy, while foundational in breast cancer treatment, confers substantial cardiotoxicity. Identifying biomarkers to guide anthracycline exemption without compromising efficacy has remained an unresolved clinical challenge for decades. METHODS: We conducted multi-cohort spatial-omics and clinical validation integrating 345 early-stage triple-negative breast cancer (eTNBC) and 167 HER2 + breast cancer patients from Fudan University Shanghai Cancer Center (FUSCC) cohorts, alongside 150 eTNBC patients from a validation cohort. Tumor-specific MHC-II (tsMHC-II) expression was quantified via multiplex immunohistochemistry (mIHC). Mechanistic insights were derived from the NeoTRIP immunotherapy spatial cohort, I-SPY2 trial data, TCGA database, ATAC-seq chromatin profiling, ChIP, and patient-derived organoid (PDO)-immune cell co-culture systems. RESULTS: In eTNBC, high tsMHC-II expression predicted improved disease-free survival (DFS) and comparable overall survival (OS) with paclitaxel-carboplatin (PCb) versus anthracycline-sequential paclitaxel (EC-P), identifying tsMHC-II as a predictive marker for anthracycline exemption. High tsMHC-II correlated with prolonged DFS and OS in both TNBC and HER2 + subtypes. Multi-omics including spatial and transcriptional cohorts revealed tsMHC-II-high tumors harbor immune-rich microenvironments with elevated cytotoxic T cells, B cells, and antigen-presenting cells. Validation in NeoTRIP and I-SPY2 cohorts demonstrated superior immunotherapy response in tsMHC-II-high patients. Mechanistically, ATAC-seq, ChIP and PDO co-culture models confirmed that KAT2B upregulated tsMHC-II via CIITA promoter acetylation, sustaining immunotherapeutic vulnerability. CONCLUSION: TsMHC-II serves as a dual biomarker for adjuvant anthracycline chemotherapy exemption and neoadjuvant immunotherapy stratification in TNBC, driven by KAT2B-mediated epigenetic remodeling. These findings advance precision strategies to reduce anthracycline toxicity while enhancing immune activation in eTNBC.