Tumor microenvironment remodeling by STING agonism sensitizes endothelial cells to cytotoxic anti-PD-L1/L2 antibody

Background: Checkpoint inhibitors targeting PD-1 and PD-L1 have revolutionized cancer immunotherapy; however, their efficacy remains limited in immune-excluded tumors characterized by scarce T-cell infiltration and a profoundly immunosuppressive tumor microenvironment (TME). Activation of the stimulator of interferon genes (STING) pathway represents a promising strategy to overcome immune exclusion by promoting TME remodeling and immune cell recruitment. This study investigated the therapeutic potential of combining 8803, a potent STING agonist with broad cross-species activity, and 27907, a novel Fc-engineered dual-specific antibody targeting PD-L1 and PD-L2, designed to enhance antibody-dependent cytotoxicity and phagocytosis. Methods: The activity of 8803 was assessed in human and murine STING reporter cell lines and in co-culture systems with tumor, endothelial, and immune cells. The Fc-mediated effector functions of 27907 were characterized through ADCC and ADCP reporter bioassays. Antitumor efficacy was evaluated in B16-PD-L2 melanoma (C57BL/6) and TS/A mammary carcinoma (BALB/c) mouse models treated with intratumoral 8803 and/or systemic 27907. Tumor growth and survival were monitored, and immune and vascular remodeling were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence. Statistical analyses were performed using two-way ANOVA with Bonferroni post-test for tumor growth, Mantel–Cox log-rank test for survival, and unpaired Student’s t-test or one-way ANOVA for in vitro and ex vivo data. Results: The combination of 8803 and 27907 resulted in significant tumor growth inhibition and prolonged survival compared with single-agent treatments. STING activation by 8803 remodeled the TME by reducing intratumoral M2-like macrophages and mature regulatory dendritic cells (mregDCs) while enhancing T-cell and myeloid cell infiltration. It also induced PD-L1 and PD-L2 upregulation on tumor and endothelial cells. The dual-specific antibody 27907 efficiently mediated antibody-dependent cellular cytotoxicity and phagocytosis, leading to selective endothelial cell killing, vascular disruption, extensive necrosis, and enhanced immune infiltration in the combination treatment group. Conclusions: Dual PD-L1/PD-L2 blockade synergizes with STING pathway activation to promote immune and vascular remodeling, resulting in superior antitumor efficacy in preclinical tumor models. These findings provide a strong rationale for the clinical development of combination strategies that integrate STING agonists with cytotoxic checkpoint antibodies to overcome immune exclusion and enhance cancer immunotherapy outcomes. Supplementary information: The online version contains supplementary material available at 10.1186/s13046-026-03711-9.