{
  "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 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.Conclusions Our 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Dominik J Schaer"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Nadja Schulthess-Lutz"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Livio Baselgia"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Kahrisan Kunasingam"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Rok Humar"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Kerstin Hansen"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Melanie Eschment"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Elena Duerst"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Florence Vallelian"
    }
  ],
  "title": "Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy",
  "uid": "67ab6c66-733b-51ac-bfcb-72d1c1f6a2d5"
}