IFI16/IFI202 blockade suppresses tumor growth through CD8(+) T-cell-mediated immunity.

BACKGROUND: Tumor-associated macrophages (TAMs) are key drivers of immunosuppressive inflammation in the breast cancer microenvironment, promoting tumor progression and resistance to immune checkpoint blockade. Our previous work identified extracellular IFI16/IFI202 as tumor-derived damage-associated molecular patterns which activate pro-inflammatory signaling in TAMs via Toll-like receptor 2, thereby facilitating immune evasion. In this study, we investigated the therapeutic potential of a monoclonal antibody (mAb) targeting extracellular IFI202 to suppress tumor-promoting inflammation and to restore antitumor immunity. METHODS: We developed a mAb against IFI202 and evaluated its functions in bone marrow-derived macrophages (BMDMs) using ELISA and western blotting. In vivo efficacy was assessed in the mouse mammary tumor virus-polyoma virus middle T-antigen breast cancer model by treating with IFI202 mAb, or anti–programmed death-1 (PD-1) antibody, as monotherapies or in combination. Tumor volume, metastasis, cytokine levels, and immune cell infiltration were analyzed. Statistical significance was assessed using Mann–Whitney U test or ANOVA, with P < 0.05 considered significant. RESULTS: Conditioned medium obtained from 4T1 breast cancer cells pre-incubated with IFI202 mAb suppressed secretion of IL-6 and TNF-α, and inhibited activation of ERK and NF-κB in BMDMs. Intraperitoneal injection of IFI202 mAb in mouse mammary tumor virus-polyoma middle T-antigen mice significantly reduced tumor growth and lung metastasis. In addition, IL-1β expression, CD8(+) T cell infiltration, and levels of granzyme B and interferon-γ, were enhanced in the tumors of IFI202 mAb-treated mice, indicating that IFI202 mAb restored cytotoxic function of CD8(+) T-cells. Combination of IFI202 mAb with PD-1 mAb significantly improved antitumor efficacy compared to monotherapy. CONCLUSIONS: Neutralization of extracellular IFI202 suppresses TAM-mediated inflammation and supports a tumor microenvironment favorable for T-cell–mediated immunity. In combination with anti–PD-1 therapy, IFI202 mAb further enhances antitumor responses, suggesting a promising and tumor-selective strategy that may help overcome resistance to immune checkpoint blockade in breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-025-02213-4.