{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:15:54Z","timestamp":1778130954121,"version":"3.51.4"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"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>Purpose<\/jats:title>\n                    <jats:p>The aim of this study was to define the interplay between K\/N-RAS mutational status, tumor immune microenvironment (TIME), and chemotherapy response in patients with proficient mismatch repair (pMMR) colorectal cancer (CRC)\u2014a population refractory to immunotherapy but constituting &amp;gt;90% of CRC cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed 225 patients with pMMR CRC. Multiplex immunohistochemistry was used to quantify stromal and intraepithelial densities of CD4\n                      <jats:sup>+<\/jats:sup>\n                      , CD8\n                      <jats:sup>+<\/jats:sup>\n                      , CD68\n                      <jats:sup>+<\/jats:sup>\n                      , and CD163\n                      <jats:sup>+<\/jats:sup>\n                      immune cells, along with expression of \u03b2-catenin, CMTM6, and programmed death-ligand 1 (PD-L1). Multivariable Cox regression and interaction tests were performed to identify prognostic and predictive biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      K\/N-RAS status stratified pMMR CRC into two distinct subtypes. In RAS wild-type tumors, high stromal CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell infiltration was independently associated with better prognosis. In RAS-mutant tumors, loss of intraepithelial CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and high CD163\n                      <jats:sup>+<\/jats:sup>\n                      macrophage density predicted poor survival. Critically, chemotherapy significantly improved overall survival only in specific subgroups, including RAS-mutant, \u03b2-catenin-low, CMTM6-low, and CD163-high patients. Formal interaction testing confirmed CD163\n                      <jats:sup>+<\/jats:sup>\n                      macrophage infiltration as a predictive biomarker for chemotherapy benefit and significant chemotherapy benefit in the CD163-high subgroup (HR\u00a0=\u00a00.20,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>RAS mutational status shapes a divergent immune landscape that dictates both prognosis and chemotherapy response in pMMR CRC. Integration of RAS status with key TIME features\u2014particularly CD163\u2014may enable the precise selection of patients most likely to benefit from chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1798858","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:56:58Z","timestamp":1778129818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RAS mutation status and immune microenvironment define distinct prognostic landscapes and predict chemotherapy benefit in pMMR colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Shigang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pathology, The Affiliated Qingyuan Hospital (Qingyuan People\u2019s Hospital), Guangzhou Medical University","place":["Qingyuan, Guangdong, 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China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Affiliated Qingyuan Hospital (Qingyuan People\u2019s Hospital), Guangzhou Medical University","place":["Qingyuan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingquan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Affiliated Qingyuan Hospital (Qingyuan People\u2019s Hospital), Guangzhou Medical University","place":["Qingyuan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Affiliated Qingyuan Hospital (Qingyuan People\u2019s Hospital), Guangzhou Medical University","place":["Qingyuan, Guangdong, 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