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

ABSTRACT 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.