A phase 2 trial evaluated neoadjuvant immunotherapy with nivolumab and ipilimumab in patients with locally advanced, mismatch repair-deficient (dMMR) colon cancer. Of 115 enrolled patients, 113 underwent timely surgery, with only 2 patients experiencing delays due to treatment-related adverse events. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), but none discontinued treatment. Among 111 patients included in the efficacy analysis, 109 (98%) showed a pathological response, including 105 (95%) with a major response and 75 (68%) with a complete response. No disease recurrences were observed after a median follow-up of 26 months. The treatment had an acceptable safety profile and led to high rates of pathological responses. The study supports the use of neoadjuvant immunotherapy in dMMR colon cancer, with promising outcomes in terms of safety and efficacy. The results suggest that neoadjuvant immunotherapy could be a viable option for patients with locally advanced dMMR colon cancer, potentially improving outcomes compared to traditional chemotherapy. The study was funded by Bristol Myers Squibb and conducted at the Netherlands Cancer Institute. The findings indicate that neoadjuvant immunotherapy is a safe and effective treatment for dMMR colon cancer, with high rates of pathological response and no disease recurrence observed. The study highlights the potential of immunotherapy in the treatment of dMMR colon cancer, particularly in patients with locally advanced disease.A phase 2 trial evaluated neoadjuvant immunotherapy with nivolumab and ipilimumab in patients with locally advanced, mismatch repair-deficient (dMMR) colon cancer. Of 115 enrolled patients, 113 underwent timely surgery, with only 2 patients experiencing delays due to treatment-related adverse events. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), but none discontinued treatment. Among 111 patients included in the efficacy analysis, 109 (98%) showed a pathological response, including 105 (95%) with a major response and 75 (68%) with a complete response. No disease recurrences were observed after a median follow-up of 26 months. The treatment had an acceptable safety profile and led to high rates of pathological responses. The study supports the use of neoadjuvant immunotherapy in dMMR colon cancer, with promising outcomes in terms of safety and efficacy. The results suggest that neoadjuvant immunotherapy could be a viable option for patients with locally advanced dMMR colon cancer, potentially improving outcomes compared to traditional chemotherapy. The study was funded by Bristol Myers Squibb and conducted at the Netherlands Cancer Institute. The findings indicate that neoadjuvant immunotherapy is a safe and effective treatment for dMMR colon cancer, with high rates of pathological response and no disease recurrence observed. The study highlights the potential of immunotherapy in the treatment of dMMR colon cancer, particularly in patients with locally advanced disease.