Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.

The treatment of triple-negative breast cancer (TNBC) poses significant challenges, necessitating innovative approaches to identify therapeutic targets. This study presents a cohort of patients with early-stage TNBC receiving neoadjuvant chemotherapy or chemo-immunotherapy, leveraging single-cell RNA sequencing and metabolic analysis to elucidate the impact of metabolic reprogramming on treatment response. Our findings reveal metabolic heterogeneity at levels of metabolic genes, pathways, and fluxes. Cell-type-specific metabolic traits show stronger associations with therapeutic response compared with bulk metabolic features and the proportion of major cell types. We identify a dynamic collaboration between tumor cells and myeloid cells driven by differential glucose utilization and lactate production, which facilitates tumor progression. Monocarboxylate transporter 1 (MCT1) inhibitors disrupt their interaction, enhancing the efficacy of anti-PD-1 and antibody-drug conjugate (ADC) treatments in TNBC mouse models. Overall, our study delineates the single-cell metabolic landscape of TNBC and positions MCT1 as a promising target.