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.

Keywords: TNFα‐TNFR2 axis; breast cancer; effector regulatory T cells; neoadjuvant chemotherapy; stress‐programmed immune states.