{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T19:13:02Z","timestamp":1791573182008,"version":"4.3.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"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><jats:title>Introduction<\/jats:title><jats:p>Microsatellite stable (MSS) colorectal cancer with liver metastases (CLRM) responds poorly to immunotherapy, and various approaches to break immune tolerance have been tried. Radiotherapy in combination with immune checkpoint inhibitors is one of promising therapies, and the choice of radiotherapy and immunotherapy modalities is also a hot issue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we report on a Phase I trial treating nine patients with MSS CLRM using a combination of high and low dose radiotherapy and immune checkpoint inhibitors (ICIs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The primary endpoint of the trial was the safety and tolerability of this combination treatment modality. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study results showed that at three dose levels\u2014single doses of 6Gy (n=3), 8Gy (n=3), and 10Gy (n=3)\u2014the most common treatment-related adverse events (TRAEs) were nausea, vomiting, fatigue, and abnormal liver function. At the first condition assessment, four patients were observed to have stable disease (SD) and one patient achieved partial response (PR). In exploratory endpoint analyses, tissue biopsies and paired hematologic samples from patients showed M2 macrophage reduction. Plasma cytokines IL-10, IL-17, and INF-\u03b1 increased after treatment with both drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In summary, this is the first clinical trial demonstrating the safety and immunogenic activity of combined high and low dose radiotherapy with ICIs in MSS colorectal cancer liver metastases (CRLMs). The combination therapy stimulated the immune response and altered the tumour microenvironment, warranting further exploration in the future.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1503517","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T05:22:17Z","timestamp":1738819337000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["High and low dose radiotherapy combined with ICIs for MSS colorectal cancer patients with liver metastases: a phase I study 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