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Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT02857569\" ext-link-type=\"uri\">NCT02857569<\/jats:ext-link>\n                    ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) or intravenous ipilimumab (3\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (T\n                    <jats:sub>reg<\/jats:sub>\n                    ) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural T\n                    <jats:sub>reg<\/jats:sub>\n                    cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fc\u03b3 receptor\u00a0(Fc\u03b3R) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated T\n                    <jats:sub>reg<\/jats:sub>\n                    cell and Fc\u03b3R\n                    <jats:sup>+<\/jats:sup>\n                    M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10341-w","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:02:17Z","timestamp":1777474937000},"page":"219-229","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Safety and efficacy of intratumoural anti-CTLA4 with intravenous 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