Journal Article

Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy

Baselgia, Livio, Duerst, Elena, Schulthess-Lutz, Nadja, Humar, Rok, Hansen, Kerstin, Vallelian, Florence, Eschment, Melanie, Schaer, Dominik J, Kunasingam, Kahrisan

2025

Overview

BackgroundTumor-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.MethodsWe 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.ResultsIn 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 the latter are NRF2-imprinted “stress-TAMs”, with immunosuppressive and tumor-promoting activity. The same NRF2 activation gradient separates pro-inflammatory CXCL9+ and anti-inflammatory SPP1+TAMs across diverse human cancers. NRF2-imprinted TAMs silence IFN-STAT1 programs, lose major histocompatibility complex-II and chemokine expression, fail to expand T cells, drive tumor cell invasion in 3D co-cultures, and foster metastasis. Constitutive hematopoietic NRF2 activation accelerated the growth of therapy-naïve MMTV-PyMT breast tumors and markedly impaired the efficacy of agonistic anti-CD40 antibody therapy in MC38 subcutaneous and lung-metastasis models. Conversely, macrophage-specific Nrf2 deletion restored immunogenic TAMs and potentiated anti-CD40 and anti-programmed cell death protein-1 treatments.ConclusionsOur data pinpoint a previously underappreciated cytoprotective mechanism, which inadvertently sustains immunosuppressive macrophages and confers therapy resistance. These results define stress-induced TAMs as an untapped driver of macrophage-based immune evasion. Inhibiting NRF2 activity alongside standard immunotherapies could restore a pro-inflammatory macrophage–T-cell amplification loop, potentially improving patient responses to T-cell—and macrophage-directed immunotherapies.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Acidosis / Adaptation / Animals / Antibodies / Antigen presentation / Basic and Translational Cancer Immunology / Cancer / Cell death / Cell growth / Female / Flow cytometry / Genes / Genetic engineering / Genotype & phenotype / Hemorrhage / Humans / Hypoxia / Immunotherapy / Immunotherapy - methods / Leukocytes / Macrophage / Metastasis / Mice / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Original Research / Oxidative stress / Radiation therapy / Transcription factors / Tumor microenvironment - TME / Tumor-Associated Macrophages - immunology / Tumor-Associated Macrophages - metabolism / Tumors