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Here we report clinical results and in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (10% or less residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Circulating tumour DNA was positive in 26 of 31 patients at baseline, and clearance was observed in 5 of 6 responders before surgery, whereas 19 of 20 non-responders remained circulating tumour DNA positive. Responses were observed despite a low tumour mutational burden in all tumours, whereas chromosomal genomic instability scores were significantly higher in responders than in non-responders. Furthermore, responding tumours had significantly higher baseline expression of proliferation signatures and TCF1, and imaging mass cytometry revealed a higher percentage of Ki-67\n                    <jats:sup>+<\/jats:sup>\n                    cancer and Ki-67\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in responders than in non-responders. These results provide a comprehensive analysis of response to neoadjuvant immune checkpoint blockade in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09679-4","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T15:04:26Z","timestamp":1760972666000},"page":"726-735","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Neoadjuvant immunotherapy in mismatch-repair-proficient colon cancers"],"prefix":"10.1038","volume":"648","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9790-9568","authenticated-orcid":false,"given":"Pedro B.","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7217-1460","authenticated-orcid":false,"given":"Yara L.","family":"Verschoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 G.","family":"van den Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1205-1895","authenticated-orcid":false,"given":"Sara","family":"Balduzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels F. 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A.J. and A.T. are employees of Natera, Inc. with stocks and\/or stock options to own in the company. A.J. also owns stocks in Iovance, Agenus and Versastem. J.B.A.G.H. is an advisor to Achilles Therapeutics, AstraZeneca, BioNTech, Bristol Myers Squibb, Curevac, Gadeta, Imcyse, Immunocore, Iovance Therapeutics, Ipsen, Merck Serono, Merck Sharp & Dohme, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, PokeAcel, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures and T-Knife; has received research grants unrelated to this study from Amgen, Asher Bio, BioNTech US, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Sastra Cell Therapy; and owns stock in Neogene Therapeutics. All grants were paid to the institution. E.E.V. reports research funding from Bristol Myers Squibb outside the current work. T.N.S. declares advisory roles for Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Therapeutics, Cell Control, Merus and Scenic Biotech; and is a venture partner at Third Rock Ventures. L.F.A.W. received project funding from Bristol Myers Squibb outside the current work. M.C. is an advisor to Bristol Myers Squibb, Kineta, Merck Sharp & Dohme, NOUSCOM and Roche\/Genentech; and has received research grants unrelated to this study from Bristol Myers Squibb, Agenus, Merck Sharp & Dohme and Roche\/Genentech. All grants were paid to the institution.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}