Stress‐Programmed Immune Niches Fuel TNFR2+ Treg Activation and Drive Neoadjuvant Chemotherapy Resistance in Breast Cancer

ABSTRACT The tumor microenvironment (TME) harbors diverse immune cell states that shape therapeutic outcomes in breast cancer. Here, we identify a conserved stress‐programmed cellular module as a key responder to neoadjuvant therapies in breast cancer, characterized by coordinated heat shock gene expression across multiple immune cells, based on single‐cell transcriptomic data from neoadjuvant chemotherapy‐treated patients. We discover that this multicellular program enhances the effector fate of regulatory T cells (Tregs) via chronic and TME‐wide TNFα signaling, compromising the efficacy of neoadjuvant chemotherapy. TNFα signaling, typically considered an antitumor cytokine, is paradoxically elevated in nonresponders both pre‐ and post‐treatment, with a particularly prominent TNFα–TNFR2 interaction. Blocking this axis, with or without chemotherapy, significantly suppresses tumor growth without observable toxicities. Our findings highlight the immune‐editing role of stress‐programmed Effector regulatory T cells, Neoadjuvant chemotherapy, Stress‐programmed immune states, TNF α ‐TNFR2 axis, breast cancercell states and support their therapeutic potential as a rational target in breast cancer.