{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:16:13Z","timestamp":1787026573481,"version":"build-2736575974"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brain metastases from colorectal cancer (CRC) are associated with poor survival and limited treatment options. As immunomodulatory therapies gain relevance, a deeper understanding of the tumor microenvironment (TME) in this setting is needed. Tumor-associated macrophages (TAMs) are pivotal regulators of tumor immunity, yet their spatial organization, polarization, and relationship to PD-L1\u2013mediated immune checkpoint regulation in CRC brain metastases remain poorly defined. We therefore characterized the compartment-specific architecture and functional orientation of TAMs in brain metastases and matched primary CRCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Immunohistochemical analyses of CD68 (pan-macrophages), CD86 (M1-associated), CD163 (M2-associated), and PD-L1 were performed on tissue microarrays from tumor specimens of 50 patients with CRC brain metastases, including 31 matched primary tumor\u2013brain metastasis pairs. Compartment-specific TAM densities and PD-L1 expression were quantified to assess intra- and intertumoral heterogeneity and correlated with clinicopathological parameters and clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both primary CRCs and brain metastases exhibited macrophage-rich TMEs characterized by stromal predominance and an M2-skewed polarization. Compared with matched primary tumors, brain metastases showed a significant stromal enrichment of CD163\n                      <jats:sup>+<\/jats:sup>\n                      TAMs. Dexamethasone treatment was associated with reduced densities of CD86\n                      <jats:sup>+<\/jats:sup>\n                      TAMs in brain metastases. PD-L1 expression was predominantly confined to immune cells and displayed marked intra- and intertumoral heterogeneity, with frequent discordance between matched primary tumors and brain metastases, including recurrent lesions. In primary CRCs, high densities of CD68\n                      <jats:sup>+<\/jats:sup>\n                      TAMs at the invasive front were associated with shortened brain metastasis\u2013free survival, whereas neither TAM infiltration nor PD-L1 expression correlated with overall survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CRC brain metastases exhibit a distinct, stroma-dominated and M2-polarized TME, consistent with site-specific enrichment of protumoral TAM phenotypes within the cerebral niche. This may reflect advanced disease biology, immunological adaptation to the brain microenvironment, or therapy- and selection-driven immune remodeling during metastatic progression. The association between dexamethasone treatment and reduced M1-associated TAM infiltration suggests therapy-related modulation of antitumoral immune activity, with potential implications for perioperative management. The heterogeneity and frequent discordance of PD-L1 expression highlight its dynamic regulation and support individualized assessment of metastatic lesions prior to immunotherapy. Collectively, these findings support site-specific immune profiling and identify TAMs as promising therapeutic targets within the TME of CRC brain metastases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1816086","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:45:35Z","timestamp":1776059135000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune architecture of colorectal cancer brain metastases: spatial TAM heterogeneity and PD-L1 dynamics"],"prefix":"10.3389","volume":"17","author":[{"given":"Lisa Marie","family":"Grape","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]},{"name":"Institute of Pathology, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Hanke","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medizinisches Versorgungszentrum (MVZ) St\u00e4dtisches Klinikum Dessau","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belal","family":"Neyazi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Rashidi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Magdalena","family":"Swiatek","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schaufler","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Alexandra","family":"Dumitru","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Vascular and Transplant Surgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Croner","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Vascular and Transplant Surgery, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mawrin","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Franke","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Otto-von-Guericke University","place":["Magdeburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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