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

## TL;DR

Stress-programmed immune cells in breast cancer promote chemotherapy resistance by activating Tregs through TNFα–TNFR2 signaling, and blocking this pathway could improve treatment outcomes.

## Contribution

The study identifies a stress-programmed immune module and its role in chemotherapy resistance via TNFα–TNFR2 signaling in breast cancer.

## Key findings

- Stress-programmed immune states are linked to elevated TNFα signaling and chemotherapy resistance in breast cancer.
- Blocking the TNFα–TNFR2 axis suppresses tumor growth without toxicity, suggesting a new therapeutic strategy.
- Single-cell data reveals coordinated heat shock gene expression across immune cells in nonresponders to chemotherapy.

## 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.

Single‐cell sequencing reveals stress‐programmed immune states driving TNFα–TNFR2–mediated Treg activation and therapy resistance in breast cancer, while targeting this axis restores antitumor immunity.