Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy.

ABSTRACT:

Background

Tumor-associated macrophages (TAMs) can switch between immune-activating and cancer-promoting states; yet, the stress pathways that lock them into procancerous states remain obscure. Here we defined the role of transcription factor NRF2 as a mediator of procancerous macrophages.

Methods

We combined spatial transcriptomics, single-cell RNA sequencing, three-dimensional (3D) cell culture and in vivo tumor models to explore how NRF2 activation status in tumor-associated macrophages modifies responses to immunotherapy.

Results

In MC38 colon tumors, repeated anti-CD40 or radiotherapy created necrosis that split TAMs into peripheral Cxcl9+ and peri-necrotic Spp1+ subsets. Spatial transcriptomics, single-cell RNA sequencing, and Keap1-deficient mice showed that th

SUBMITTER: Schaer DJ 

PROVIDER: S-EPMC12581087 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature