Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m² day 1, bolus 5-fluorouracil 500 mg/m² and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases (n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases (n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190.