{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:14:28Z","timestamp":1783314868192,"version":"3.54.6"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced colorectal cancer (aCRC), but clinical benefit remains largely confined to patients with deficient mismatch repair (dMMR). Responses among patients with proficient mismatch repair (pMMR) are heterogeneous, underscoring the need for accessible biomarkers that can refine patient stratification beyond MMR status. Histopathological features on routine hematoxylin and eosin (H&amp;amp;E)-stained slides may reflect the immune and stromal architecture of the tumor microenvironment. This study investigated the prognostic value and treatment-outcome associations of standardized stromal tumor-infiltrating lymphocytes (sTILs), tumor-stroma ratio (TSR), and tumor budding (TB) in patients with aCRC treated with ICIs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective multicentre study included 210 patients with pathologically confirmed aCRC who received PD-1\/PD-L1\u2013based immunotherapy between January 2021 and June 2025. H&amp;amp;E-stained sections were independently assessed by two blinded pathologists. The primary endpoint was progression-free survival (PFS), with objective response rate (ORR) and overall survival (OS) as secondary endpoints. Survival outcomes were analyzed using Kaplan\u2013Meier estimates and Cox proportional hazards models. Inter-observer agreement was evaluated using Cohen\u2019s kappa.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At a median follow-up of 22.4 months, high sTILs (\u226520%) were associated with a significantly higher ORR than low sTILs (47.2% vs. 15.2%, P&amp;lt;0.001). Patients with low stromal content (TSR \u226550%) experienced longer median PFS compared with those with high stromal content (10.8 vs. 5.2 months; HR 0.48, 95% CI 0.35\u20130.66; P&amp;lt;0.001). Within the pMMR subgroup (n=162), the combination of high sTILs and low TSR identified an immune-active phenotype with an ORR of 38.5% versus 6.1% in patients with neither feature. Multivariable analysis confirmed high sTILs (HR 0.47, 95% CI 0.26\u20130.84; P\u00a0=\u00a00.011) and high-grade tumor budding (HR 2.03, 95% CI 1.39\u20132.96; P&amp;lt;0.001) as independent prognostic factors for PFS, while TSR demonstrated prognostic value in univariate analysis only.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Standardized assessment of routine H&amp;amp;E-stained histopathological features provides clinically relevant prognostic and outcome-stratifying information in ICI-treated patients in aCRC. These cost-effective biomarkers may complement molecular testing, particularly for stratifying pMMR patients in real-world immunotherapy settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1811658","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T04:21:15Z","timestamp":1783311675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Histopathological biomarkers of immunotherapy outcome in advanced colorectal cancer: a multicentre retrospective study"],"prefix":"10.3389","volume":"16","author":[{"given":"Jianying","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Jiangxi Medical College","place":["Shangrao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, Jiangxi 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