Abstract A047: Harnessing localized anti-cancer treatments for systemic anti-metastatic tumor responses in aged mice through the combination of local anti-CD40 agonist and cGAMP/irradiation

Abstract Immune checkpoint inhibitors and systemic chemotherapy have limited efficacy in metastatic cancers, particularly in elderly patients, and are associated with significant toxicity. Localized therapies, such as irradiation and STING agonists, have the potential to elicit systemic anti-tumor immune responses but remain clinically suboptimal. Strategies to fully leverage the systemic benefits of localized treatments are yet to be established. Here, we show that local delivery of anti-CD40 agonist, in combination with irradiation or cGAMP, effectively eradicates distant metastatic tumors in young and aged mice, an effect unattainable with single-agent therapies. Irradiation and cGAMP enhance antigen-presenting cell activation and NK cell infiltration, driving regression of primary tumors, while CD40 stimulation promotes DC1 migration to tumor-draining lymph nodes, priming tumor-specific T cells by suppressing FoxP3+ regulatory CD4+ T cells and expanding T-bet-expressing CD4+ and CD8+ T cells. Notably, the combination of anti-CD40 and STING agonists reprograms the myeloid compartment into a distinct pro-inflammatory state, marked by high Ly-6C expression and increased production of IL-12, type I/II interferons, and GM-CSF. This reprogramming further promotes the induction of CD4+CD8+ double-positive cytotoxic T cells and NK cell infiltration, ultimately driving robust tumor rejection. These findings present a novel localized therapeutic strategy that synergizes with current immunotherapies and offers promising advancements in cancer treatment. Citation Format: Minglu Yan, Zhijian "james" Chen. Harnessing localized anti-cancer treatments for systemic anti-metastatic tumor responses in aged mice through the combination of local anti-CD40 agonist and cGAMP/irradiation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A047.