Background: Immune checkpoint inhibitors (ICI), such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) or nivolumab (anti-programmed cell death protein 1) have been proven to be an effective strategy in solid cancers. However, ICI seem not to be effective in microsatellite stable (MSS) cancers. As they might lack an immunogenic priming, radiotherapy (RT) is capable to induce an immunogenic cell death (ICD) and subsequently an immunogenic tumor immune microenvironment (TIME). Thus, RT might restore the susceptibility of MSS tumors to ICI and consequently leading to an effective anti-tumor immune response. Methods: This is a prospective, randomized, open-label, multicenter, phase II investigator-initiated clinical trial (IIT), including patients with locally advanced rectal cancer (LARC). Patients receive either neoadjuvant chemoradiotherapy (CRT) alone (50 Gy in 2 Gy fractions over 25 working days + capecitabine 1650 mg/m²/d PO) or in combination with ipilimumab (1 mg/kg IV on day 7) and nivolumab (3 mg/kg IV on day 14, 28 and 42). Patients will undergo surgery within 10-12 weeks post CRT. The primary endpoint is incidence of treatment-emergent adverse events (AEs) assessed by the Clavien-Dindo classification of surgical complications and the common terminology criteria of adverse events (CTCAE). Secondary objectives are radiographic and pathological therapy response. Serial liquid (plasma, serum and peripheral blood mononuclear cells) and tissue biopsies will be taken before, during and after neoadjuvant treatment. Genomic, transcriptomic, epigenomic and proteomic pattern of liquid and tissue biopsies, as well as the immune cell infiltrate of resected specimen, will be correlated with therapy response and clinical outcome. Currently 8 of planned 80 patients have been enrolled. Registration numbers: NCT no. NCT04124601, EudraCT no. 2019-003865-17. Clinical trial information: NCT04124601