Anti-CD4 antibody treatment increases the number of and activates tumor-specific CD8+ T cells by depleting immunosuppressive cell populations (such as CD4+Foxp3+ T cells), thus suppressing tumor growth in mice [Ueha et al, Cancer Immunol Res, 3:631 (2015)]. Co-administration of anti-CD4 antibody with other immune stimulators can further augments its anti-tumor efficacy. Here, we co-administered an alarmin, high mobility group nucleosome binding protein 1 (HMGN1), with an anti-CD4 antibody. In the Colon26 subcutaneous tumor model, anti-CD4 antibody with low-dose HMGN1 (< 0.2 mg/mouse, i.p.) synergistically suppressed tumor growth comparing to untreated and single-treated controls (p< 0.001). In mice receiving the combination treatment, CCR7+ migratory dendritic cells (mDCs) expressed higher level of co-stimulatory receptors (CD80 and CD86), and the number of CCR7+ mDCs and CD8+CD137+PD-1+ T cells further increased in the tumor. Collectively, these results suggest that low-dose HMGN1 may mobilize and activate the CCR7+ migratory DCs and tumor specific CD8+ T cells in the tumor. Combination treatment with low-dose HMGN1 and CD4 depleting antibody represents a new strategy to treat solid tumors. Triple combination immunotherapy with PD-1/PD-L1 immune check point blockade could result in further improved anti-tumor efficacies.