Synergistic activation of STING and CD40 in the tumor microenvironment enhances CD8+ T-cell-dependent antitumor immunity

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and activates antigen-presenting cells (APCs) to promote immune responses through producing inflammatory cytokines such as interleukin (IL)-12 and TNFα. Although cancer immunotherapies using agonistic anti-CD40 antibody have been conducted in clinical settings, many clinical trials have been discontinued owing to the occurrence of severe adverse effects. Stimulator of interferon genes (STING) also promotes activating APCs to prime tumor antigens to effector T cells. Recent our studies have shown that intratumoral administration of the STING ligand cyclic GMP-AMP (cGAMP) effectively activated tumor-specific T cells and suppressed tumor growth in mouse models. Based on these findings, we hypothesized that co-activation of both STING and CD40 within the tumor microenvironment could effectively suppress tumor growth and prolong survival in tumor-bearing hosts. In the present study, CD40 expression was upregulated in mouse bone marrow-derived dendritic cells (BMDCs) upon stimulation with cGAMP, and this effect was dependent on TNFα induced by type I IFNs produced in an autocrine and paracrine manner. Furthermore, in mouse tumor models, CD40 was found to be critical for the antitumor effects of STING-targeted therapy, and intratumoral co-activation of STING and CD40 synergistically suppressed tumor growth and prolonged survival in a CD8⁺ T-cell-dependent manner. These findings suggest that intratumoral immunotherapy co-targeting STING and CD40 represents a promising therapeutic strategy with potentially reduced systemic side effects.