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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Ahmad Salameh,
  • Elisabetta Bolli,
  • Manuela Iezzi,
  • Christine Gagliardi,
  • Laura Conti,
  • Chiara Cossu,
  • Paul Blezinger,
  • Alessia Lamolinara,
  • Andrew Lewis,
  • Michael A. Curran,
  • Federica Cavallo,
  • Federica Pericle

摘要

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.