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@ARTICLE{Pavlov:307457,
      author       = {S. Pavlov and E. Ali and F. Ambrozkiewicz and W. Ye and M.
                      Rajtmajerová and V. Liška and K. Hemminki$^*$ and A.
                      Trailin},
      title        = {{M}acrophages in {C}olorectal {C}ancer: from {N}ormal
                      {M}ucosa to {D}istant {M}etastasis: {B}eyond the {M}1/{M}2
                      {P}aradigm.},
      journal      = {Journal of cancer},
      volume       = {17},
      number       = {1},
      issn         = {1837-9664},
      address      = {Wyoming, NSW},
      publisher    = {Ivyspring Internat. Publ.},
      reportid     = {DKFZ-2025-03056},
      pages        = {157 - 176},
      year         = {2026},
      abstract     = {Colorectal cancer (CRC) is the third most common malignancy
                      and leading cause of mortality worldwide. Tumor
                      microenvironment (TME) strongly influences CRC growth,
                      immune evasion, and metastasis. Among various immune cells,
                      tumor-associated macrophages (TAMs) act as key regulators of
                      cancer progression. Although traditionally classified as M1
                      (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory,
                      pro-tumor), single-cell RNA sequencing and spatial
                      transcriptomics have revealed that macrophage phenotypes
                      exist along a continuum, challenging the classic dichotomy.
                      This review investigates macrophages throughout CRC
                      development, from normal mucosa to adenoma, primary tumor,
                      and liver metastasis. Early adenomas feature M1-like
                      macrophages that drive local inflammation, whereas advanced
                      adenomas and invasive CRC comprise M2-like macrophages
                      promoting angiogenesis, extracellular matrix remodeling, and
                      immunosuppression. TAMs are crucial in CRC metastasis,
                      particularly to the liver. M2-polarized Kupffer cells
                      express CD206 and CD163, secrete hepatocyte growth factor,
                      and activate PI3K/AKT signaling, thus aiding extravasation,
                      survival, and proliferation of metastatic cells. They also
                      foster lymphangiogenesis and immunosuppression through
                      release of IL-10 and TGF-β. CRC's consensus molecular
                      subtype (CMS) impacts the profile of TAMs: CMS1
                      (microsatellite instability-high) tumors typically harbor an
                      anti-tumor M1 macrophages, while CMS4 (mesenchymal) tumors
                      are enriched in M2-like TAMs, which facilitate stromal
                      remodeling and angiogenesis, ultimately contributing to a
                      poor prognosis. Spatial distribution also matters. Abundant
                      M1 macrophages at the invasive margin correlate with better
                      outcomes, whereas M2 macrophages in tumor centers and
                      metastatic sites drive disease progression. Some CD206+
                      macrophages, however, support vascular normalization, which
                      can limit metastasis. These findings underscore the
                      complexity of TAMs in CRC and highlight the necessity of
                      multi-marker phenotyping. Given the limitations of the M1/M2
                      paradigm, advanced techniques such as spatial
                      transcriptomics and single-cell RNA sequencing offer novel
                      insights into TAM heterogeneity. Future therapeutic
                      strategies targeting TAMs, including metabolic
                      reprogramming, epigenetic modulators, and immune checkpoint
                      inhibitors, hold promise for improving CRC patient outcomes
                      by shifting the balance toward an anti-tumor immune
                      response.},
      subtyp        = {Review Article},
      keywords     = {M1/M2 markers (Other) / adenoma-colorectal cancer-liver
                      metastasis sequence (Other) / colorectal cancer (Other) /
                      normal mucosa (Other) / prognostic significance. (Other) /
                      tumor microenvironment (Other) / tumor-associated
                      macrophages (Other)},
      cin          = {C020 / Z999},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331 / I:(DE-He78)Z999-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41438574},
      pmc          = {pmc:PMC12719567},
      doi          = {10.7150/jca.126772},
      url          = {https://inrepo02.dkfz.de/record/307457},
}