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This study aims to investigate the antitumor effect of non-\u03b1-biased IL-2 combined with CpG\/\u03b1-OX40 in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using 4T1 breast cancer and CT26 colon cancer models, we evaluated the antitumor effects of combining CpG\/\u03b1-OX40 with a non-\u03b1-biased IL-2 variant via both intratumoral and subcutaneous routes. Tumor growth, lung metastasis, immune profile, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      function analysis were assessed through flow cytometry, transcriptomic analysis, and T cell suppression assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combination therapy significantly inhibited primary and distant tumor growth and reduced lung metastasis in 4T1 models. Subcutaneous administration induced complete tumor regression in 55% (5\/9) of CT26-tumor-bearing mice and conferred durable tumor-specific memory. Mechanistically, the treatment enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\u2009cell activation, metabolic reprogramming, and IFN-\u03b3 production, while suppressing MDSC expansion and immunosuppressive function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that non-\u03b1-biased IL-2 synergizes with CpG\/\u03b1-OX40 to overcome microenvironmental immunosuppression and achieve systemic antitumor immunity via a subcutaneous route, offering a translatable combinatorial strategy for immune-cold tumors.<\/jats:p>\n                  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