Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
Stromal-Derived IL-8 Promotes M2 Macrophage Polarization via the RhoA/MRTF-A/SRF Transcriptional Axis to Impair CD8+ T Cell Cytotoxicity in Lung Cancer.
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Gu Xuyu, Fang Qiyu, Yu Jia, Yu Ting, Shi Huashan, Jin Kaiqi, Jiang Lei, Zhang Wentian
Аннотация
BACKGROUND: Building upon our previous finding that tumor-derived lactate activates DESMIN+ cancer-associated fibroblasts (CAFs) to secrete interleukin-8 (IL-8), this study investigates the downstream IL-8/C-X-C motif chemokine receptor 2 (CXCR2) axis in CAF-mediated macrophage polarization and lung cancer (LC) progression.
METHODS: Orthotopic and subcutaneous tumor models were established in immunocompetent and immunodeficient mice using LC, CAFs, or murine tumor organoids (MTO). Global and myeloid-specific Cxcr2 knockout models, in vitro co-cultures (macrophages, CD8+ T cells, and tumor cells), and patient-derived organoid (PDO) systems were employed.
RESULTS: DESMIN+ CAFs were the predominant source of IL-8 and promoted tumorigenesis and M2-like macrophage accumulation via the IL-8/CXCR2 axis. Genetic deletion of Cxcr2, myeloid-specific knockout, or pharmacological blockade reduced M2-like macrophage polarization through the PI3K/AKT/RhoA/MRTF-A/SRF pathway, restored CD8+ T cell effector function, and suppressed tumor progression. CXCR2 blockade also synergized with chemotherapy and anti-PD-L1 immunotherapy in murine models. In human PDO co-cultures with matched DESMIN+ CAFs and autologous CD8+ T cells, CXCR2 inhibition attenuated M2-like polarization and enhanced T cell-mediated killing of tumor organoids.
CONCLUSION: DESMIN+ CAFs drive an immunosuppressive tumor microenvironment in LC through IL-8/CXCR2 signaling and downstream MRTF-A activation. Targeting this axis represents a promising strategy to overcome treatment resistance in LC.
METHODS: Orthotopic and subcutaneous tumor models were established in immunocompetent and immunodeficient mice using LC, CAFs, or murine tumor organoids (MTO). Global and myeloid-specific Cxcr2 knockout models, in vitro co-cultures (macrophages, CD8+ T cells, and tumor cells), and patient-derived organoid (PDO) systems were employed.
RESULTS: DESMIN+ CAFs were the predominant source of IL-8 and promoted tumorigenesis and M2-like macrophage accumulation via the IL-8/CXCR2 axis. Genetic deletion of Cxcr2, myeloid-specific knockout, or pharmacological blockade reduced M2-like macrophage polarization through the PI3K/AKT/RhoA/MRTF-A/SRF pathway, restored CD8+ T cell effector function, and suppressed tumor progression. CXCR2 blockade also synergized with chemotherapy and anti-PD-L1 immunotherapy in murine models. In human PDO co-cultures with matched DESMIN+ CAFs and autologous CD8+ T cells, CXCR2 inhibition attenuated M2-like polarization and enhanced T cell-mediated killing of tumor organoids.
CONCLUSION: DESMIN+ CAFs drive an immunosuppressive tumor microenvironment in LC through IL-8/CXCR2 signaling and downstream MRTF-A activation. Targeting this axis represents a promising strategy to overcome treatment resistance in LC.