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 checkpoin
APA
Lim GY, Ka NL, et al. (2026). IFI16/IFI202 blockade suppresses tumor growth through CD8 T-cell-mediated immunity.. Breast cancer research : BCR, 28(1), 27. https://doi.org/10.1186/s13058-025-02213-4
MLA
Lim GY, et al.. "IFI16/IFI202 blockade suppresses tumor growth through CD8 T-cell-mediated immunity.." Breast cancer research : BCR, vol. 28, no. 1, 2026, pp. 27.
PMID
41484641
Abstract
[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 < 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.
[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 < 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.