KK2DP7 Stimulates CD11b ⁺ Cell Populations in the Spleen to Elicit Trained Immunity for Anti‐Tumor Therapy

Abstract The induction of trained immunity for anti‐tumor therapy represents an emerging frontier in immunotherapy research, though its mechanistic underpinnings remain poorly understood. Adjuvant‐induced trained innate immune responses constitute a critical yet underexplored component of adjuvant mechanisms of action. Here, KK2DP7, a dendrimer‐structured peptide derived from the immunomodulatory antimicrobial peptide DP7 (VQWRIRVAVIRK) is employed, as a model adjuvant to establish standardized protocols for investigating adjuvant efficacy and mechanisms in enhancing anti‐tumor immunity via trained immunity. Initial studies revealed that KK2DP7 administration significantly delayed tumor growth post‐inoculation in murine models. The comprehensive analysis demonstrated that splenic cells exhibited cardinal features of trained immunity, whereas splenectomized mice exhibited complete loss of this protective effect. Strikingly, the adoptive transfer of CD11b ⁺ cells isolated from the non‐lymphoid splenic compartment of KK2DP7‐trained mice to naïve recipients conferred robust tumor suppression. Mechanistic investigations linked this phenomenon to TLR2‐IRF7 axis activation and epigenetic reprogramming of CD11b ⁺ cells, as evidenced by chromatin accessibility assays and histone modification profiling. These findings not only unveil a novel therapeutically actionable dimension of trained immunity, centered on spleen‐resident CD11b ⁺ cell reprogramming but also establish a standardized protocol framework for systematically investigating adjuvant mechanisms in the context of trained innate immunity.