The biological functions and mechanisms of oncogenic KRASG12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC. Display omitted •Oncogenic KRAS promotes an immune-suppressive profile in CRC•IRF2 is a key downstream target of oncogenic KRAS-mediating immune suppression•IRF2 suppresses MDSC migration and infiltration by targeting the CXCL3-CXCR2 axis•Enforced IRF2 expression or CXCR2 inhibition overcomes anti-PD1 resistance in CRC Liao et al. show that oncogenic KRAS represses IRF2 expression leading to high expression of CXCL3, which binds CXCR2 on MDSCs to promote their migration into the tumor microenvironment. Enforced IRF2 expression or CXCR2 blockade overcomes resistance of tumors expressing oncogenic KRAS to anti-PD-1 therapy.